N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors

ABSTRACT

Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. TNF converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. The present invention provides low molecular weight, non-peptide inhibitors of matrix metalloproteinases (is) and TNF-α converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection having the formula  
                 
 
     wherein R 2  and R 3  form a heterocyclic ring and A is S, S(O), or S(O)2, and R 1  and R 4  are defined herein.

[0001] This application is a continuation in part of U.S. patent application Ser. No. 09/026,372, filed on Feb. 19, 1998 which claims the benefit of priority of U.S. Provisional Application No. 60/038,899 filed on Feb. 27, 1997.

BACKGROUND OF THE INVENTION

[0002] Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, scirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection. For recent reviews, see: (1g) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5(12): 1287-1196.

[0003] TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid artritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance and HIV infection in addition to its well documented antitumor properties. For example, research with anti- TNF antibodies and tralsgenic animals has demonstrated that blocking the formation of TNFc inhibits the progression of arthritis. This observation has recently been extended to humans as well.

[0004] It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. While a variety of MMP and TACE inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic and peptide-like compounds that one would expect to have bioavailability and pharmacokinetic problems common to such compounds tat would limit their clinical effectiveness. Low molecular weight, potent, lona acting, orally bioavailable inhibitors of MMPs and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states.

[0005] Recently, two references have appeared (U.S. Pat. No. 5,455,258 and European Patent Appl. 606,046) that disclose arylsulfonamido-substituted hydroxyarnic acids. These documents cover compounds exemplified by CGS 27023A. These are the only non-peptide matrix metalloproteinase inhibitors disclosed to date.

[0006] Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of general formula 1. These compounds were prepared to study the Mannrich reation. Subsequently, they were tested for their fungicidal activity.

[0007] Some sulfone carboxylic acids are disclosed in U.S. Pat. No. 4,933,367. Those compounds were shown to exhibit hypoglycemic activity.

SUMMARY OF THE INVENTION

[0008] The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (bms) and TTNF-α converting enzye (TACE) for the treatment of a rthrtis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistace) and BIV infection.

[0009] In accordance with this invention there is provided a group of compounds of general formula I

[0010] wherein:

[0011] R¹ is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0012] alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or twow groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵;

[0013] aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0014] cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0015] saturated or unsattrated 5 to 10 membered mono orbicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵;

[0016] or heteroaryl-(CH₂)₀-6— wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R⁵;

[0017] A is —S—, —SO— or SO₂—;

[0018] R² and R³ , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionally having one or two double bonds;

[0019] R⁴ is hydrogen,

[0020] alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0021] alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵;

[0022] alky2nyl of 3 to 18 carbon atoms having 1 to 3 triple b ds, optionally substituted with one or two groups selected independently from R⁵;

[0023] phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵;

[0024] C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵;

[0025] saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyde containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵;

[0026] R⁵ is H, C₇-C₁₁ alkanoyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alIyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ akyloxy, C₁-C₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, atyloxy-Ciq alkyl amine, C₁-C₁₂ perfluoro alkyl, S(O),—C₁-C₆ alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR6R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryI, -NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH2, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycde containing one heteroatom selected from O, S or NR⁷, wherein C₁C alkyl is straight or branched, heteroaryl is a 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

[0027] R⁶ is H, C, to C₁₈ allyl optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, Cl to C₆ perfluoro alkyl, S(O).-C₁-C₆ alkyl S(O), aryl where n is 0, 1 or 2;,

[0028] or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from haloen, cyano, amino, nitro, C₁-C₆ alky, C₁-C₆ alkoxy, or hydroxy;

[0029] and R⁷ is C₇- C₁₁ aroyl, C₁-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl, S(O)—-C₁-C₆-alkyl, S(O)n-aryl where n is 0, 1 or 2; COO—C₁-C₆-alkyl, COOaryL CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃, SO₂NHheteroaryl, SO2NHCOaryl,

[0030] CONHSO—C₁-C₆-alkyl, CONHSO,aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected

[0031] independently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0032] alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵;

[0033] alkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently fom R⁵;

[0034] heteroarylallyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R⁵;

[0035] biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R⁵;

[0036] arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵;

[0037] cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R⁵;

[0038] saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C₁-C₆ alkyl, optionally substituted with one or two groups selected independently from R⁵; or R2 ⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;

[0039] and the pharmaceutically acceptable salts thereof.

[0040] A more preferred aspect of the present invention is the group of compounds of general formula (Ia):

[0041] wherein:

[0042] R¹ is akyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0043] alkenyl of 3 to 18 carbonlatoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵;

[0044] aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R⁵;

[0045] cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one to two groups selected independently from R⁵;

[0046] saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR⁷, optionally substituted with one to two groups selected independently from R⁵;

[0047] or heteroaryl-(CH₂)₀₋₆— wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R⁵;

[0048] A is —S—, —SO— or SO₂—;

[0049] R² and R³, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionally having one or two double bonds;

[0050] R⁴ is hydrogen,

[0051] alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0052] alkenyl of 3 to I8 caron atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵;

[0053] alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵;

[0054] phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵;

[0055] C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵;

[0056] R⁵ is H, F, Cl, Br, I, CN, CHO, CRC₁-1 aroyl, C₂-C₆ alkanoyl, Cl to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆-alkylamino-C₁-C₆-alkoxy, C₁-C₂-alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₂perfluoro alkyl, S(O)n—C₆ alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO—C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COO—C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, NR⁶CONR⁶R⁶, NHSO₂CF₃, SOIN~heteroaryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH2, OH, aryl, heteroaryl, C₃ to Cs cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7;

[0057] wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C₁ ₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

[0058] R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, Cl to C₆ perfluoro alkyl, S(O), alkyl or aryl where n is 0, 1, or 2; or COheteroaryl;

[0059] wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

[0060] and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl, S(O),-alkyl, S(O)n-aryl where n is 0, 1 or 2; COalkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃, S2NHheteroaryl, S02 HCOaryl,

[0061] CONHSO₂alkyl, CONHSO₂aryl, aryl, heteroaryl; wherein C₁-C₆ alkyl is straiht or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, Cl6 alkoxy, or hydroxy;

[0062] alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0063] alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵;

[0064] alynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵;

[0065] arylalkyl of 7 to 16 carbon atoms, wherein aqyl is optionally substituted with one or two groups selected independently from R⁵;

[0066] heteroarylalkyl wherein ailyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R⁵;

[0067] biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R⁵;

[0068] arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵;

[0069] cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted with one or twosgroups selected independently from R⁵;

[0070] saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C 1-C₆ alkyl, optionally substituted with one or two groups selected independently from R⁵;

[0071] R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alyl where R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;

[0072] and the pharmaceutically acceptable salts thereof.

[0073] The most preferred group of compounds are those of the following formula (Ib):

[0074] in which

[0075] R¹ is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl, optionally substituted with C₁-C₆ alkl, C₁-C₆ alkoxy, C₆-Clo aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, halogen; or S(O)_(n)—C₁C₆alky1 C₁-C₆ alkoxyaryl or C₁-C₆ alkoxyheteroaryl;

[0076] A is —S—, O or —SO₂—;

[0077] R² and R³, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionally having one or two double bonds;

[0078] R⁴ is hydrogen,

[0079] alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0080] alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵;

[0081] alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵;

[0082] phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵;

[0083] C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵;

[0084] R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C, to C₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alknyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl, S(O)n-C₁-C₆ alkyl, S(O)n— aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaxrl, OCONR⁶, COOH, COO Cl— C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO2aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to Cs cycloalkyl; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

[0085] R⁶ is H, Cl to C₈ alkyl optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O), alkyl or aryl where n is 0, 1 or 2; or

[0086] COheteroaryl; wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

[0087] and R⁷ is C₁- 1 aroyl, C.₆ alkanoyl, C₁-C₂ perfluoro alkyl, S(O)n-alky1, S(O)n-aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR⁶, CONR⁶R⁶,

[0088] CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO2NHheteroaryl, SO₂NHCOaryl, CONHSO₂alkyl, CONHSO₂aryl, aryl, or heteroaryl; where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—Cl1C₆ alkyl;

[0089] alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0090] alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵;

[0091] alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵;

[0092] arylalkyl of 7 to 16 carbon atoms, optionally substituted with one or two groups selected independentIy from R⁵;

[0093] heteroarylalkyl wherein allyl is from 1 to 6 carbon ato,ms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is opiionally substituted with one or two groups selected independently from R⁵;

[0094] biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0095] arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0096] cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R⁵;

[0097] saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR—C₁-C₆ alkyl, optionally substituted with one or two groups selected independently from R⁵;

[0098] R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independently selected from C₁-C₆ alkl or R⁸ and R⁹ together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containng an oxygen atom, wherein the aryl group is phenyl or naphthyl;

[0099] and the pharmaceutically acceptable salts thereof.

[0100] The most preferred matrix metalloproteinase and TACE inhiig compounds of this invention are:

[0101] 1-benzyl4(4methoxy-benzenesulfonyl)-piperidinecarboxylic acid hydroxyamide,

[0102] 4 (methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidie-4-carboxylic acid hydroxyamide,

[0103] 1-(3,4chlorobenzyl) 4(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamide,

[0104] 4-(4methoxy-benzenesulfonyl)-1-(4methylbenzyl)-piperidinen-4-carboxylic acid hydroxamide,

[0105] 4-(4methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylic acid hydroxamide,

[0106] 1-biphenylfylmethyl(4methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide,

[0107] 4-(4methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide,

[0108] 1-(4bromo-benzyl)4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0109] 4-(4methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperline-4-carboxylic acid hydroxyamide,

[0110] 1-tert-butyl-4-(4methoxy-benzenesulfonyl)-piperidine-4carboxylic acid hydroxyamide,

[0111] 1-butyl-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0112] 1-cyclooctyl(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0113] 1-ethyl4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0114] 1-isopropyl4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0115] 1-methyl4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0116] 1-benzyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0117] 1-(4fluorobenzyl)4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0118] 1-(fluorobenzyl)4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0119] 4-(4methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

[0120] 4-(4-methoxy-benzenesulfonyl)- 1-[2-(4-methoxyphenyl)ethyl]-piperidine-4-carboxylic acid hydroxyamide,

[0121] 4-(4metoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide,

[0122] 4-(4n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

[0123] 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4carboxylic acid hydroxyamide,

[0124] 4-(4n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propy)-piperidine-4-carboxylic acid hydroxyamide,

[0125] 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide,

[0126] 4-(4n-butoxy-benzenesulfonyl)- 1 -(2-phenoxythyl)-piperidine-4-carboxylic acid hydroxyarmide,

[0127] (4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide,

[0128] 1-Benzyl-4-(4benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0129] 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-ylmethoxy)- benzyl]-piperidine-4-carboxylic acid hydroxyamide,

[0130] 4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl- 1-ylethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide,

[0131] 1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0132] 1-Ethyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0133] 1-n-Butyl4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0134] 4[(4chloro-phenoxy)-benzenesulfonyl] 1 -methyl-piperidine-4-carboxylic acid hydroxyamide,

[0135] 4[4-(4chloro-phenoxy)-benzenesulfonyl1]-ethyl-piperidine-4-carboxylic acid hydroxyamide,

[0136] 1-Butyl4-(4chlorophenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyarnide,

[0137] 1-Benzyl-4-[4-(4-chlorophenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,

[0138] 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,

[0139] 1-Butyl[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,

[0140] 1-Benzyl-74-4-(2-ethyl-butoxy)-benzenesulfonyl1-piperidine-4-carboxylic acid hydroxyamide,

[0141] 4-(4butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

[0142] 4-(4Methoxy-benzenesulfonyl)-1-(4thiophen-2-y1-benzyl)-piperidine-4-carboxylic acid hydroxyanmide,

[0143] 4-(4-methoxy-benzenesulfonyl)-1-(4pyridin-2-y1-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

[0144] 1-(3,4Dichlorobenzyl)4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[0145] [(4Chloro-benzyloxy)-benzenesulfonylJ-1-methylpiperidie4-carboxylic acid hydroxamide,

[0146] 4-(4Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxamide,

[0147] [4-(4Chloro-benzyloxy)-benzenesulfonyl]- 1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide,

[0148] (4Butoxy-benzenesulfonyl)-1-(4methylbenzyb-piperidine-4 carboxylic acid hydroxamide,

[0149] 4-(4Butoxy-benzenesuIfonyl)-1-(4cyanobenzyl)-piperidine-4-carboxylic acid hydroxamide, and

[0150] 4-(Butoxy-benzenesulfonyl)-1-pyridinlylmethyl-piperidine-4-carboxylic acid hydroxamide, and pharmaceutical salts thereof.

[0151] It is understood that the definition of the compounds of formulas I, Ia and lb, when RI, R², R³ and R⁴ contains asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which posses the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possesses the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques. Where not stated otherwise, the term “alkyl” refers to a straight or branched C₁-C₆ allyl group and aryl is phenyl or naphthyl. The pharmaceutically acceptable salts are those derived from pharmaceutically acceptable organic and inorganic acids such as lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, suluic, methanesulfonic, and similarly known acceptable acids.

[0152] The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of compound of this invention and a pharmaceutically acceptable carrier.

[0153] The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients.

[0154] In order to obtain consistency of administraton, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules, and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg per kg. Such composition may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.

[0155] The compositions of the invention may be formulated with conventional excipients, such as fillers, a disintegrating agent, a binder, a lubricant, a flavoring agent, and the like. They are formulated in conventional manner.

[0156] Also according to the present invention, there are provided processes for producing the compounds of the present invention.

PROCESS OF THE INVENTION

[0157] The compounds of the present invention may be prepared according to one of the general processes out lined below.

[0158] The appropriately substituted mercaptan derivative was alkylated using either substituted (Scheme I) or unsubstituted ( Scheme 2) α-bromo acetic acid ester derivative in refluxing acetone using CO₃ as base. The sulphide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH₂Cl₂ or by using Oxone in methanol/ water. The sulfone obtained from the above mentioned process can be either furter alrylated using variety of alkyl halides to obtain the disubstituted derivative or it can be hydrolyzed using NaOH/MeOH at room temp. However instead of using the ethyl ester, if the tertiary butyl ester is present, the hydrolysis can be carried out with TFA/CH₂Cl₂ at room temperature. Subsiquendy, the carboxylic acid obtained was converted to the hydroxamic acid derivative by reaction with oxalyl chloride/ DMX (catalyc) and hydroxyl aminel triethyl amine.

[0159] As outlined in Scheme 3, the sulfide derivative can be further alkrlated using lithium bis(trimethyl silyl)amide in THF at 0° C. The allylated or mono substituted compound was hydrolyzed and converted to the hydroxamic acid derivative. The sulfinyl derivatives were prepared by oxidizing the sulfide hydroxamic acid derivatives with H₂O₂ in MeOH solution.

[0160] The corresponding 1-substituted4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamides were prepared starting from diethanolarnine and appropriately substituted alkyl or aryl halides (Scheme 4). The N-substituted diethanol amine derivatives were converted to the dichloro compounds using thionyl chloride. The corresponding dichlorides were reacted with substituted sulfonyl acetic acid ethyl ester derivatives in the presence of K₂CO₃/18-Crown-6 in boiling acetone. 1-substituted4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl esters thus obtained were converted to the hydroxy amide as outlined in Scheme 4. Altematively these classes of compounds and other hetrocycles can be prepared as indicated in Scheme 5 and 6.

[0161] Alternatively, Schemes 7 to 11 show methods for the preparation of hydroxamic acid compounds using a solid phase support (P).

[0162] Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 <s5 eq.); l,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b) Thiol (5.0 eq.); a ~sodium iodide (5.0 eq.); 1 ,8-diazabicyclo[5.4.0]undec47ne (DB U, 3.0 eq.); WAIF; 25° C.; 12-16 hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. d) mCPBA (5.0 eq.); iiI; 25° C.; 12-24 hours. e) ThA: DCM (1:1); 25° C.; 1 hour.

[0163] The 4-O-methylhydroxylamine-phenoxymethylcopoly(styrene 1%-divinylbenzene)-resin (hydroxylamine resin) may be coupled with a 2-halo acid to give the hydroxamate ester resin. The coupling reaction may be carred out in the presence of carbodiinide, such as DIC, in an inert solvent such as DMF at room temperature. The halogen group may be dssplaced is with a thiol in the presence of a base, such as DBU, in an inert solvent such as 1tFat room temperature. The sulfide may be oxidized to the sulfoxide by reaction with an oxidizing agent such as tert-butylhydroperoxide in the presence of an acid catalyst such as benzenesulfoniic acid, in an inert solvent such as DCM at room temperature. Alternatively, the sulfide may be oxidized to the sulfone by reaction with an oxidizing agent such as metachloroperoxybenzoic acid, in an inert solvent such as DCM at room temperature. The sulfide, sulfoxide, or sulfone may be treated with and acid, such as tifluoroacetic acid, in and inert solvent such as DCM to liberate the free hydroxamic acid.

[0164] Scheme 8 shows a method of preparing hydroxamic acids having alkoxy groups attached to the aromatic ring.

[0165] Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiiiide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b) 4-Fluorobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5A.0]undec-7ene (DBU, 3.0 eq.); THIF; 25° C.; 12-16 hours. c) Alcohol (15.0 eq.); sodium hydride (15.0 eq.); DMF; 80° C.; 15 hours, d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25° C.; 12-24 hours. f) TFA:DCM (1:1); 25° C.; 1 hour.

[0166] The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by fluorobenzenethiol as previously described. The fluoro group may then be displaced with an alcohol in the presence of a base such as sodium hydride, in an inert solvent such as DNT at about 80° C. The alkoxybenzenesulfanyl hydroxamnate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxarmate ester as previously described. The free hydroxamic acids may beulberated as previously described. Scheme 9 shows a method of preparing 2-bisarylsulfany1-, sulfiny1-, and sulfonylhydroxamic acids.

[0167] Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b) 4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0]undec-70ene (DBU, 3.0 eq.); THF; 25° C.; 12-16 hours. c) 70% tert-butylhydroperoxide (40eq.); benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25° C.; 12-24 hours. e) Arylboronic acid (2.0 eq.); tetrakis(triphenylphosphine) palladium(0) (0.1 eq.); 10% aqueous sodium carbonate (10.0 eq.); DME,; 80° C.; 8 hours. f) TFA : DCM (1:1); 25° C.; 1 hour.

[0168] The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by bromobenzenethiol as previously described. The bromobenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described The bromo group may then be replaced with an aryl group by reaction with the arylboronic acid in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium(0), and a base such as sodium carbonate, in an inert solvent such as DME at about 80° C. The free hydroxamic acids may be iberated as previously described.

[0169] Scheme 10 shows a method of preparing hydroxamic acids having amine groups attached to the aromatic ring.

[0170] Reagents anld Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiide DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b) 4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5A.0]undec-7-ene DBU, 3.0 eq.); THF; 25° C.; 12-16 hours. c) Amine (20.0 eq.); tris(dibenzylideneacetone)-dipalladium dipalladium(0) (0.2 eq.); (S)—(—)-2,2′-bis(diphenylyphosphimo) 1,1′-binaphthyl ((S)-BINAP, 0.8 eq.); sodium tert-butoxide (18.0 eq.); dioxane; 80° C., 8 hours; d) TFA: DCM (1:1); 25° C.; 1 hour.

[0171] The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by bromobenzenethiol as previously descniei The bromo group may then be displaced with an amine in the presence of a catalyst such as tds(dibenzylideneacetone)-dipalladium(0) and a ligand such as (S)-BINAP and a base such as sodium tert-butoxide, in an inert solvent such as dioxane at about 80° C. The free hydroxamic acids may be liberated as previously described.

[0172] Scheme 11 shows a method of preparing hydroxamic acids having sulfonate groups attached to the aromatic ring.

[0173] Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3Eiisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b) 4-Hydroxybenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25° C.; 12-16 hours. c) Sulfonyl chloride (5.0 eq.); triethylamine (2.0 eq.); DCM; 25° C.; 8 hours. d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 250C; 12-24 hours. f) TFA: DCM (1:1); 25° C.; 1 hour.

[0174] The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may to be displaced by hydroxybenzenethiol as previously described. The hydroxybenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described The hydroxy group may then be sulfonylated by reaction with a sulfonyl chloride in the presence of a base such as triethylamine, in an inert solvent such as DCM at about room temperature. The free hydroxamic acids may be liberated is as previously described.

[0175] The following examples are presented to illustrate rather than limit the scope of the invention.

[0176] HPLC purity of compounds prepared by combinatorial procedures is presented as area percentage at a prescribed wavelength (% @ nm).

EXAMPLE 1

[0177] N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide

[0178] To stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mnmol) and anhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), ethyl 2-bromo-propionate (3.6 gm, 20 mrnmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, reaction was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated The residue was extracted with chloroform and washed with H₂O and 0.5 N NaOH solution. The organic layer was further washed well with water, dried over MgSO₄, filtered and concentrated to afford 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester as a light yellow oil. Yield 4.5gms (94%); MS; 241 (M+H)+.

[0179] To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (2.44 g, 10 mmol), in THF (100 ml) at 4° C., lithium bis(trimethylsilyl)amide (1 M solution, -15 ml, 15 mmol) was added slowly. The orange colored reaction mixture was stirred at room temperature for 15 minutes and then it was cooled to 0° C. at which time it was stirred for an additional hour. The temperature of the mixture was again brought to 40° C. and benzylbromide (1.72 gm, 10 mnmol) was added dropwise in THF. The reaction was warmed to room temperature and stirred overnight before it was quenched with ice water, extracted with chloroform and washed with water. The organic layer was dried over MgSO₄, filtered and concentrated and chromatographed on a silica-gel column with 10% ethyl acetate:hexane to afford 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield: 860 mg, (26%); MS: 331 (M+H)⁺.

[0180] 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester (4.12 g, 12 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml) was added. The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated, diluted with 1:1 hexane:diethyl ether and extracted with H₂0. The water layer was cooled with ice and acidified to pH 3. The acid was then extracted with chloroform and the organic layer was dried over MgSO₄, filtered and concentrated to afford of 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a low melting solid. Yield 580 mg, 16%; MS: 303.2 (M+H)+. To a stirred solution of 2-(4rmethoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid (0.5 g, 1.65 mmol) and DMF (2 drops) in CH₂C₁₂ (100 ml) at O° C., oxalyl chloride (1.0 gmn, 8 ammol) was added in a drop-wise manner. After the addition, the reaction mixture was stirred at room temperature for 1 hour. Simultaneously, in a separate flask a mixture of hydroxylamine hydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of CH₂C₁ ₂ and added slowly to the hydroxylamine at OC. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was extracted with chloroform and washed well with water. The product obtained was purified by silica gel column chromatography and eluted with ethyl acetate. The N-hydroxy-2-(4-methoxyphenylsulfanyl)-2-methyl-3-pheny1-propionamide was isolated as a colorless solid. mp 88 ° C.; Yield, 300 mg, 57%; MS: 318 (M+H)+; 1H NMR (300 Miz, CDC₁ ₃): 6 1.32 (s, 3H), 3.07 (d, J=11 Hz, 1H), 3.23 (d, J=11 Hz, IH), 3.79 (s, 3H), 6.83-7.36 (m, 9H).

EXAMPLE 2 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide

[0181] 2-4-Methoxyphenylsulfanyl)-phenylacetic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl α-bromophenyl acetate (7.18 g, 31.4 mmol) and 4-methoxythiophenol (4.4 g, 31.4 mmol), 8.5 g of the product was isolated as a light yellow oil. Yield 90%; MS: 303.1 (M+H)⁺.

[0182] 2(4-Methoxy-phenylsulfanyl)-2-phenyl acetic acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-phenyl-acetic acid ethyl ester (3.0 g, 10 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as in Example 1. Yield 1.9 g, 70%. Low melting solid. MS: 273 (M+H)⁺.

[0183] Starting from 2-(4-methoxy-phenylsulfanyl)-phenyl acetic acid (1.05 g, 3.83 m'mol) and following the procedure as outlined in Example 1, 154 mg of N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide was isolated as a colorless solid. mp 155 ° C.; Yield 14%; MS: 290 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 3.72 (s, 3H), 4.68 (s, 1H), 6.86-7.44 (m, 9H).

EXAMPLE 3 2-(4Methoxy-phenylsulfanyl)-2,5 dimethyl-hex4enoic acid hydroxyamide

[0184] 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex4enoic acid'ethyl ester was prepared following the procedure of Example 1, second paragraph. Starting from (4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (3.5 g, 14.3 mmol), and isoprenyl bromide (2.25 g, 15 mmol), 2.2 g of the product was isolated as an oil. Yield 50%; MS: 310 (M+H)⁺. 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex4noic acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex~enoic acid ethyl ester (2.0 g, 6.4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1. Yield is 1.9 g, 99% of low melting solid. MS: 280 (M+H)⁺.

[0185] Starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hexAenoic acid (I1;67 g, 5.8 mmol) and following the procedure as outlined in Example 1, 1.5 g of 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide was isolated as a colorless solid. mp 89 ° C.; Yield 94%; MS: 296 (M+H)⁺; IH NMR (300 MHz, CDC₁ ₃): 5 1.34 (s, 3H), 1.61 (s, 3H), 1.74 (s, 3H), 2.41-2.58 (m, 2H), 3.80 (s, 3H), 5.17 (t, J=7.5 Hz, 1H), 6.86 (d, J=12.4 Hz, 2H), 7.35 (d, J=12.4 Hz, 2H).

EXAMPLE 4 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide

[0186] 2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mnol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated Yield 99%; Light yellow oil; MS: 271 (M+H)⁺. 2-(4Methoxy-phenylsulfanyl)-3-methyl-butync acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester (5.8 g, 21.6 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 1. Yield 5.0 g, 99%. Low melting solid. MS: 242 (I+H)⁺. Starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (4.39 g, 18.3 mmol) and following the procedure as outlined in Example 1, 1.5 g of N-hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide was isolated as a colorless solid. mp 119 ° C.; Yield 33%; MS: 256 (M+H)⁺; IH NMR (300 MHz, DMSO-d₆): 3 0.90-1.07 (m, 6H), 1.84-1.96 (m, 1H), 3.07 (d, J=8.8 Hz, IH), 3.75 (s, 3H), 6.88 (d, J=15 Hz, 2H), 7.35 (d, J=15 Hz, 2H).

EXAMPLE 5

[0187] N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-methyl-3-phenyl-propionamide N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide (400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol (100 ml) and 30% H₂0₂ (10 ml) was added. The reaction mixture was stirred for 48 hours at room temperature at which time it was cooled to o0° C. and quenched with saturated Na₂SO₃ (20 ml) solution. The reaction mixture became cloudy. It was stirred for 4 hours before it was concentrated in a room temperature water bath, diluted with water, extracted with CHCl₃ and washed with H₂O.The organic layer was dried over MgSO₄, filtered and concentrated The tide compound was isolated by silica gel column chromatography, eluting with 75% ethylacetate:hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H)⁺; lH NMR (300 Mz, CDC₁₃): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).

EXAMPLE 6 2-(4Methoxy-benzenesulfinyl)-2,5dimethyl-hex41enoic acid hydroxyamide

[0188] Starting from 2-(4-methoxy-benzenesulfanyl)-2,5 dimethyl-hexenoic hydroxamide (900 mg, 3.0 mnmol) (prepared in Example 3) and following the procedure outlined in Example 5, 2-(4-methoxy-benzenesulfinyl)-2,5dimethyl-hex-4-enoic acid hydroxyamide was isolated as a colorless solid. Yield: 104 mg (10%); mp 108 ° C.; MS: 312 (M+H)⁺; IH NM (300 MHz, DMSO-d₆): 5 0.88 (s, 3H), 1.59 (s, 3H), 1.68 (s, 3H), 2.27-2.80 (m, 2H), 5.02 (t, J 7.5 Hz, 1H), 7.09 (d, J=9 Hz, 2H), 7.39 (d, J=9 Hz, 2H).

EXAMPLE 7 N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramide

[0189] Stating from N-hydroxy-2-(4-methoxy-phenylsulfanyl)-3-niethyl-butyramide (1 g, 3.9 mmol) as prepared in Example 4, and following the procedure of Example 5, N-hydroxy-2-(4-methoxy-benzenesulfmyl)-3-methyl-butyramide was isolated as a colorless solid. Yield: 420mg (40%); mp 163 ° C.; MS: 272 (M+H)⁺; ¹H NMR (30Q.MHz, DMSO-d₆):δ0.89-1.12 (m, 6H), 1.63-1.74 (m, 1H), 3.13 (d, J=7 Hz, 1H), 3.83 (s, 3H), 6.94-7.65 (m, 4H).

EXAMPLE 8 N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide

[0190] Starting from N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide (240 mg, 0.83 mmol) as prepared in Example 2, and following the procedure outlined in Example 5, N-hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide was isolated as colorless solid. Yield: 100 mg (40%); mp 135 ° C.; MS 304 (M+H)⁺; IH NMR (300 MH, DMSO-d6): 3 3.75 (s, 3H), 4.38 (s, 1H), 6.92-7.69 (m, 9H)

EXAMPLE 9 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide.

[0191] To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) and anhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), at-bromo ethyl acetate (3.3 gm, 20 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H₂O and 0.5 N NaOH solution. The organic layer was flrther washed well with water, dried over MgSO₄, filtered and concentrated. (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%); MS; 227 (M+H)⁺.

[0192] To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0 gm, 40 mmol) in methylene chloride (100 rml) at 0° C., (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester (4.4 g, 20 miol) in CH₂C₁ ₂ (15 ml) was added slowly. The reaction mixture turned cloudy and was stirred at room temperature for 6 hours. The reaction mixture was then diluted with hexanes (3001 ml) and stirred for 15 minutes. The solids were filtered off and Na₂SO₃ solution was added to the organic layer which was stirred for at least 3 hours before the mixture was extracted with CHCl₃ and washed with H₂O.The organic layer was dried over MgSO₄, filtered and concentrated and the colorless (4-methoxy-phenylsulfonyl)-acetic acid ethyl ester was isolated as an oil. Yield: 100%; MS: 259.1 (M+H)⁺.

[0193] To stirred solution of the (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.5 g, 10 mmol), benzyl bromide ( 1.8 gm,10 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K₂CO₃ (IOggms, excess) and the mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO₄, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethyl acetate: hexane. The product, 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was isolated as a low melting solid. Yield: 3.0 gm 86%; Low melting solid; MS: 349 (M+H)⁺.

[0194] To a stirred solution of 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (348 mg, 1 mmol) in methanol (25 ml), 10 N NaOH (10 ml) was added. The reaction mixture was stirred at room temperature for 48 hours. At the end, the reaction mixture was concentrated and carefullly neutralized with dilute HCI. The residue obtained was extracted with chloroform, s washed well with water, dried and concentrated The product obtained was purified by silica-gel column chromatography by eluting with ethyl acetate: methanol (95:5) to afford 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid as a colorless oil. Yield: 250 mg, 89%; MS: 321 (M+H)⁺.

[0195] Starting from 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (200 mg, 0.625 mmol) and following the procedure as outlined in Example 1, 150 mg of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide was isolated as a brown solid. Yield: 71%; mp 180 PC; MS: 336 (M+H)⁺; IH NoM (300 MD, CDC₁ ₃): 5 3.2 (m, 1H), 3.8 (s, 3H), 4.04.2 (m, 2H), 7.0-8.0 (m, 9H).

EXAMPLE 10 2-(4-Methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide

[0196] 2-(4-Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Startg from ethyl 2-bromo hexanoate (7 g, 32 mmol) and 4-methoxybenzenethiol (4.2 g, 30 mmol), 8.3 g of the product was isolated. Yield 98%; Light yellow oil; MS: 283 (M+H)⁺.

[0197] Starting from 2-(4-methoxy-phenylsulfanyl)-hexanoic acid ethyl ester. (2.8 g 10 mmol) and following the procedure as outlined in Example 9, 3 g of 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester was isolated as a colorless solid. Yield: 95%; mp 62 ° C.; MS: 314 (M+H)⁺.

[0198] Starting from 2-(4medioxy-benzenesulfonyl)-hexanoic acid ethyl ester (2 g, 6.3 mmol) 1.5 g (83%) of 2-(4-methoxy-benzenesulfonyl)-hexanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp 116 ° C.; MS: 287 (M+H)⁺.

[0199] Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid (1.0 g, 3.1 mmol) and following the procedure as outlined in ExampIe 1, 700 mg of 2-(4-methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide was isolated as a colorless solid. Yield: 60%; mp 130 OC; MS: 302 (M+H) ⁺; ¹H NMR (300 MD, CDC₁ ₃): 8 0.786 (t, J=7.2 Hz, 3H), 1.1 -1.3 (m, 4H), 1.6-1.8 (m, 2H), 3.7 (m, 1H), 3.9 (s, 3H),7.2 (d, J=11 Hz, 2H), 7.8 (d, J=11 Hz, 2H), 9.3 (s, IH), 10.9 (s, IH).

EXAMPLE 11 2-(4-Methoxy-benzene sulfonyl)-teradecanoic hydroxyamide

[0200] 2-(4-Methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from the corresponding ethyl -2-bromomyristate (5.0 g, 14.9 mmol) and 4-methoxythiophenol (1.9 g, 13.4 mmol), 5.0 g of the product was isolated. Yield 98%; Light yellow oil; MS: 393 (M+H)⁺. Starting from 2-(4-methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester. (3.9 g 10 mmol) 1 5 and following the procedure as outlined in Example 9, 3.2 g of 2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid ethyl ester was isolated as a colorless solid. yield: 76%; Oil; MS: 425 (M+H)⁺. Starting from 2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid ethyl ester (2.5 g, 5.9 mmol), 2.0 g (85%) of 2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. mp 82 ° C.; MS: 397 (M+H)⁺. Starting from 2-(4-methoxy-benzene sulfonyl)-tetradecanoic acid (1.14 g, 2.9 mmol) and following the procedure as outlined in Example 1, 670 mg of 2-(4-methoxy-benzenesulfonyl)-tetradecanoic hydroxyamide was isolated as an off-white solid. Yield: 57%; mp 114 ° C.; MS: 414 (M+H)⁺; ¹H NMR (300 Miz, DMSO-d6): 8 0.85 (t, J=7 Hz, 3H), 1.16-1.27 (m, 20 H), 1.66 (m, 2H), 3.62-3.70 (m, 1H), 3.87 (s, 3H), 7.12 (d, J=15 Hz, 2H), 7.73 (d, J=I5 Hz, 2H).

EXAMPLE 12 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamide

[0201] To a stirred solution of 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (1.0 gm, 3mmol) (example 9), methyl iodide ( 1 ml, excess) and 18-Crown-6 (500 mg) in acetone (250 ml), K₂CO (10 gm, excess) was added and the reaction mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO₄, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexanes to afford 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield 1.0 g, 98%; MS: 349 (M+H)⁺.

[0202] Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester (900 mg, 2.7 mmol), 850 mg (quantitative) of 2-(4-methoxy-benzenesulfonyl)-2-methyl- 3 phenyl-propionic acid was isolated by following the procedure as outlined in Example 9. Colorless oil, MS 335 (M+H)⁺.

[0203] Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid (900 mg, 2.7 nmmol) and following the procedure as outlined in Example 1, 450 mg of N-hydroxy-2-(4 methoxybenzenesulfonyl)-2-methyl-3-phenyl-propionamide was isolated as a brown solid. Yield: 48%; mp 58 ° C.; MS: 350 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 8 1.4 (s, 3H), 3.1 (d, J=9 Hz, 1H), 3.6 (d, J=9 Hz, IH), 3.9 (s, 3H), 6.8 - 7.8 (m, 911).

EXAMPLE 13 2-(4-Methoxy-benzenesulfonyl)-2,5-dimethyl-hexenoic acid hydroxyamide

[0204] Starting from 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (Example 1) (12 g; 50 mmol) and following the procedure as outlined in Example 9, 12 g of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester was isolated as a semi-solid. yield 100%; MS: 256.1 (M+H)⁺.

[0205] Following the procedure as outlined in Example 12, 2-(4-methoxy-benzenesulfonyl)-2,4-dimethyl-hex-4-enoic acid ethyl ester was prepared, starting from (1 g, 3.6 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and isoprenyl bromide (1.0 g, 6 mmol). Yield 1.0 g, 81%; Colorless oil; MS: 341 (M+H)⁺.

[0206] Starting from 2-(4-methoxy-benzenesulfonyl)-2,5-diinethyl-hex-4-enoic acid ethyl ester (900 mg, 2.6 mmol) 800 mg (96%) of 2-(4-methoxybenzenesulfonyl)-2,5-dimethyl-hexenoic acid was isolated as a semi solid by following the procedure as outlined in Example 9. MS: 3.13 (M+H)⁺.

[0207] Starting from 2-(4-methoxy-benzenesulfonyl)-2,5 diethyl-hex-4-enoic acid (1 g, 3.2 mmol) and following the procedure as outlined in Example 1, 700 mg of 2-(4-methoxy-benzenessulfonyl)-2,5 dimethyl-hex-4-enoic acid hydroxyamide was isolated as a low melting s solid Yield: 67%; MS: 328 i+H)⁺ ¹H NMR (300 z, CDCl₃): 5 1.3 (s, 3H), 1.5 (d, J=6.2 Hz, 6H), 2.5 -3.0 (m, 2H), 3.9 (s, 3H), 7.0 (d, J=11 Hz, 2H), 7.8 (d, J=11 Hz, 2H).

EXAMPLE 14 3-(Biphenyl-4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

[0208] Following the procedure as outlined in Example 12, 3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and 4 (chloromethyl)biphenyl (2.5 as 12 mmol). Yield 4.0 g, 91%; Colorless oil; MS: 438 (M+H)⁺.

[0209] Starting from 3-(biphenyl~yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acid ethyl ester (3 g, 6.8 mmol), 2.5 g (89%) of 3-(biphenyl4yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. mp 161 IC; MS: 411 (M+H)⁺.

[0210] Starting from 3-(biphenyl4yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (2.0 g, 4.8 mmol) and following the procedure as outlined in Example 1, 1.2 g of 3-(biphenyl4i yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide was isolated as colorless solid. Yield: 58%; mp 177 ° C.; MS: 426 (M+H)⁺; ¹H NMR (300 MIz, CDCI₃): 5 1.4 (s, 3H), 3.2 (d, J=9 Hz, IH), 3.7 (d, J=9 Hz, IH), 3.9 (s, 3H), 7.0 - 7.8 (m, 13H), 9.7 (bs, IH).

EXAMPLE 15 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca4,8-dienoic acid hydroxyamide

[0211] Following the procedure as outlined in Example 12, 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca4,8ienoic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and geranyl bromide (3.0 et 13 mmol). Yield 4.0 g, 98%; Colorless oil; MS: 409 (M+H)⁺.

[0212] Starting from 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyldeca-4,8Aienoic acid ethyl ester (3 g, 7.4 mmol), 2.8 g (96%) of 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyldeca-4,8-dienoic acid was isolated as a colorless oil by following the procedure as outlined in Example 9. MS: 379 (M−H)⁻. Starting from 2-(4-methoxy-benzenesulfonyl)2,5,9-trimethyldeca-4,8-dienoic acid (2.0 g, 5.2 mmol) and following the procedure as outlined in Example 1, 1.8 g of 2-(4-methoxy-benzenesulfonyl)2,5,9-trimethyl-deca4,⁸-dienoic acid hydroxyamide was isolated as a colorless oil. Yield: 88%; MS: 396 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 8 1.4 (s, 3H), 1.6 (s, 3H), 1.65 (s, 3H), 1.7 (s, 3H), 2.0- 3.1 (m,6 H), 3.9 (s, 3H), 5.5 (m, 2H), 6.98 (d, J=9.0 Hz, 2H), 7.7 (d, 3=9.0 Hz, 2H).

EXAMPLE 16 3-Cyclohexy1-N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-propionamide

[0213] Following the procedure as outlined in Example 12, 3-cyclohexy1-2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and bromomethylcyclohexane (1.8 g, 10 mmol). Yield 3.5 g, 95%; Yellow oil; MS: 369 (M+H)⁺.

[0214] Starting from 3-cyclohexy1-2(4-methoxy-benzenesulfonyl)2-methyl propionic acid ethyl ester (3 g, 8.1 inmol) 2.5 g (90%) of 3-cyclohexy1-2-(4-methoxy-benzenesulfonyl)2-methyl propionic acid was isolated as colorless solid by following the prooedure as outlined in Example 9. mp 116 ° C.; MS: 341 (M+H)⁺.

[0215] Starting from 3-cyclohexy1-2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid (2.0 g, 5.8 mmol) and following the procedure as outlined in Example 1, 1.1 g of 3-cyclohexy-1-N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-propionamide was isolated as colorless solid. Yield: 55%; mp 58 ° C.; MS: 356 (M+H)⁺; ¹H NM (300 MHz, CDCl₃) 5 1.4 (s, 3H), 2.3 -1.0 (m, 13 H), 3.9 (s, 3H), 7.0 (d, 8.8 Hz, 2H), 7.69 (d, 9.0 Hz, 2H).

EXAMPLE 17 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-E4-(2-piperidin-1-y1-ethoxy)phenyl]-propionamide

[0216] Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)2-methyl 3-[4-(2-piperidin-1-y1-ethoxy)phenyl]-propionic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and the 4-(2-piperidin-1-y1-ethoxy)benzyl chloride (2.9 g, 10 mmol). Yield 4.8 g, 98%; Brown oil; MS: 490 (M+H)⁺.

[0217] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[s(2-piperidin-1-ylethoxy) phenyl]-propionic acid ethyl ester (4.0 Em 7.9 mmol) 3.5 g (Yield: 94%) of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 106 ° C.; MS: 462.5 (M+H)⁺.

[0218] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-y1-ethoxy) phenyl]-propionic acid (2.0 g, 4.2 mmol) and following the procedure as outlined in example 1, -1 g of 1N-hydroxy- 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)phenyl]-propionamide was isolated as colorless solid. Yield: 1 g, 48%; mp 98° C.; MS: 477 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): 8 1.2 (s, 3H), 3.5 - 1.5 (m, 16 H), 3.9 (s, 3H), 4.4 (m, IH), 6.5 - 7.8 (m, 8H), 10.8 (bs, IH).

EXAMPLE 18 2-[4-(2-Azepan-1-y1-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)propionic acid hydroxyamide

[0219] Following the procedure as outlined in example 12, 2-[4-(2-azepan-1-y1-ethoxy)benzyl]-2-(4 methoxy-benzenesulfonyl)propionic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2-(4rmethoxy-benzenesulfonyl)propionic acid ethyl ester and the 1-[2-(4 chloromethyl-phenoxy)ethyl]-azepane (3.03 g, 10 mmol). Yield 4.5 g, 90%; Brown oil; MS: 504 (M+H)⁺.

[0220] Starting from 2-[4-(2-azepan-1-y1-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester (4.0 gm, 7.9 mmol) 3.5 g (Yield: 94%) of 2-[(2-azepan-1-ylethoxy) benzyl]-2-(4-methoxy-benzenesulfonyl)propionic acid was isolated as semi-solid by following the procedure as outlined in example 9. MS: 476 (M+H)⁺.

[0221] Starting from 2- [4-(2-azepan-1-yl -ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)propionic acid (2.0 g, 4.2 mmol) and following the procedure as outlined in example 1, 1 g of 2-[s(2-azepan-1-y1-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)propionic acid hydroxyamide was isolated as colorless solid. Yield: 1.8 g, 87%; mp 68° C.; MS: 491 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): 6 1.23 (s, 3H), 3.5 - 1.7 (in 18 H), 3.8 (s, 3H), 4.2 (m, IH), 6.4 - 7.89 (m, 8H), 10.9 (bs, 1H).

EXAMPLE 19 2-[(2-Azepan-1-ylethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)pentanoic acid hydroxyamide

[0222] 2-[4-(2-Azepan-1-y1-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)pentanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Starting from 2-(4-methoxy-benzenesulfonyl)pentanoic acid ethyl ester (3.5 g, 11.7 nol) and 1-[2-(4-chloromethyl-phenoxy)ethyl]-azepane (3.9 g, 12.8 nmmol). Yield 2.58 g (42%); brown oil; MS: 532.4 (M+H)⁺.

[0223] 2-[4-(2-Azepan-1-y1-ethoxy)benzyl]-2-(4-methoxy-benzetesulfonyl)pentanoic acid was prepared starting from 2-[4-(2-azepan- 1 -y1-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl) pentanoic acid ethyl ester (2 g, 3.76 mmol) dissolved in methanol 300 ml) and 10 N NaOH (15 ml). The resulting mixture was worked up as outlined in example 1. Yield 830 mg (44%); brown solid; mp 55 ° C.; MS: 504.4 (M+H)⁺.

[0224] Starting from 2-[4-(2-azepan-1-y1-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)pentanoic acid (690 mg, 1.37 mmol) and following the procedure as outlined in example 1, 240 mg of 2-[4-(2-azepan-1-y1-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)pentanoic acid hydroxyamide was isolated as ayellow solid. Yield 34%; mp 85 ° C.; MS: 519.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): d 0.71 (t, J=7.3 Hz, 3H), 0.78-1.77 (m, 16 H), 3.043.46 (m, 4H), 3.87 (s, 3H), 4.26 (m, 2H) 6.87 (d, J=8.7 Hz, 2H), 7.14 (m, 4H), 7.71 (d, J=9 Hz, 2H), 9.07 (s, 1H), 10 (s, IH).

EXAMPLE 20 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-N,Ndsopropyl amino-ethoxy)phenyl]-propionamide

[0225] Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and the 4-(2-N,liisopropyl amino-ethoxy)benzyl chloride (6.1 g, 20 mmol). Yield 8.9 g, 88%; Yellow oil; MS: 506.5 (M+H)⁺.

[0226] Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropyl amino-ethoxy)phenyl1-propionic acid ethyl ester (4.0 gm, 7.9 mmol) 3.5 g (Yield: 92%) of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[(2-N,N-iisopropyl amino-ethoxy)phenyl-1-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 68 ° C.; MS: 478.6 (M+H)⁺.

[0227] Startng from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[(2-N,N-diisopropyl amino-ethoxy)phenyl]-propionic acid (2.0 g, 4.1 mmol) and following the procedure as outlined in example 1, 1 g of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-C₄(2-N,N-diisopropyl amino-ethoxy)phenyl]-propionamide was isolated as colorless solid. Yield: 1 g, 49%; mp 98° C. (Hcl Salt); MS: 493 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 1 k.2 (s, 3Hi), 1.3 (d,6H), 1.4 (d,6H), 3.5 - 1.5 (m, 6 H), 3.9 (s, 3H), 4.4 (s, 2H), 6.5 - 7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 21 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy) -phenyl]-propionamide

[0228] Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy)phenyl]-propionic acid ethyl ester was prepared, starting from (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)benzyl chloride (5.5 g, 20 mmol). Yield 8.5 g, 89%; Brown oil; MS: 478.6 (M+H)⁺.

[0229] Starting from 2-4-methoxy-benzenesulfonyl)2-methyl-3-[(2-N,Ndethyl aminoethoxy) phenyl]-propionic acid ethyl ester (3.5 gm, 7.7 mmol) 3.0 g (Yield: 85%) of 2-(4-methoxy-benzenesulfonyl)2-methyl-3->[4-(2-N,Niethyl amino-ethoxy)phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 96-98° C.; MS: 450.5 (M+H)⁺.

[0230] Starting from 2-4-methoxy-benzenesulfonyl)2-methyl-3-(4-(2-N,ethyl amin(ethoxy) phenyl1-propionic acid (2.0 g, 4.4 mmol) and following the procedure as outlited in example 1, 1 g of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy) -phenyl]-propionamide was isolated as colorless solid. Yield: 1 g, 48%; mp 56-59° C. (HC₁ Salt); MS: 465.5 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 5 1.1 (t, 6H), 1.3 (s,3H), 3.2 - 3.9 (m, 8 H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5 - 7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 22 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide

[0231] Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-ylethoxy)phenyl]-propionic acid ethyl ester was prepared, starting from (5.2 g, 20 mrnol) of 2-(4-methoxy-benzenesulfonyl)propidnic acid ethyl ester and the 3-(2-piperidin-1-y1-ethoxy)benzyl chloride (6.0 g, 20 imnol). Yield 8.2 g, 83%; Brown oil; MS: 490 (M+H)⁺.

[0232] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-piperidin-1-y1-ethoxy) phenyl]-propionic acid ethyl ester (6.0 gm, 12.2 mmol) 4.9 g (Yield: 79%) of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-piperidin-1-yl -ethoxy)-phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 112 ° C.; MS: 462.5 (M+H)⁺.

[0233] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-piperidin-1-yl-ethoxy) -phenyl]-propionic acid (3.0 g, 6.5 mmol) and following the procedure as outlined in example 1, 1.8 g of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)phenyl]-propionamide was isolated as colorless solid. Yield: 1.8 g, 58%; mp 74° C.; MS: 477 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): o 1.25 (s, 3H), 1.6-1.8 (m, 6 H), 2.5 - 3.7 (m, 8H), 3.9 (s, 3H), 4.4 (t, 2H), 6.7 - 7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 23 3-(4-3-[(3-Chloro-phenyl)piperazin-1-yl1-propoxy1-phenyl)N-hydroxy-2-(4-m ethoxy-benzenesulfonyl)2-methyl-propionamide

[0234] Following the procedure as outlined in example 12, 3-(4-{3-[4-(3-chloro-phenyl)piperazin-1-yl]-propoxy}-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid ethyl ester was prepared, starting from (2.72 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and the I-[2-(4chloromethyl-phenoxy)ethyl] (3-chloro-phenyl)piperazine (4.2 g, 11 rnmol). Yield 5.5 g, 89%; Brown oil; MS: 616 (M+H)⁺.

[0235] Starting from 3-(4-{3-[(3-chloro-phenyl)piperazin-1-yl]-propoxy}-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid ethyl ester (4.0 gm, 6.5 mmol) 3.0 g (Yield: 78%) of 3-(4-{3-[4-(3-chloro-phenyl)piperazin-1-yl]-propoxy}-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 196 ° C.; MS: 588.1 (M+H)⁺.

[0236] Starting from 3-(4 { 3-[4-(3-chloro-phenyl)piperazin-1 -yl]-propoxy } -phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid (3.0 g, 5.1 mmol>a'nd following the procedure as outlined in example 1, 1.8 g of 3-(4-{3-[4-(3-chloro-phenyl)piperazin-1-yl]-propoxy}-phenyl)N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-propionanude was isolated as pale yellow solid. Yield: 1.8 g, 55%; mp 122° C. (HCl Salt); MS: 640 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 5 1.2 (s, 3H), 3.4 - 1.5 (m, 14 H), 3.9 (s, 3H), 4.5 (m, 2H), 6.5 - 8.2 (m, 12H), 10.3 (bs, 1H).

EXAMPLE 24 2-(4-Methoxy-benzenesulfonyl)5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)benzyl]-hex-4-enoic acid hydroxyamide

[0237] To a stirred solution of (4-methoxy-benzenesulfonyl)acetic acid ethyl ester (5.16 g, 20 mmol), isoprenyl bromide (3.0 g, 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and the mixture refluxed foe 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO₄, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2-(4-methoxy-benzenesulfonyl)5-methyl-hexf enoic acid ethyl ester was isolated as a colourless oil. Yield: 3.0 g, 93%.

[0238] Following the procedure as outlined in example 12, 2(4-Methoxy-benzenesulfonyl)-5-methyl-2-f4-(2-morpholinly1-ethoxy)benzyl]-hex-4-enoic acid ethyl ester was prepared, starting from (3.26 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)5-methyl-hex-4-enoic acid ethyl ester and 4-(2-morpholin-1-y1-ethoxy)benzyl chloride (3.0 , 11 mmol). Yield 4.5 g, 82%; Brown oil; MS: 546 (M+H)⁺.

[0239] Starting from 2-(4-Methoxy-benzenesulfonyl)5-methyl-2-[s(2-morpholinfy1-ethoxy) benzyl]-hex-4-enoic acid ethyl ester (3.0 gIm, 5.5 mmol) 2.1 g (Yield: 75%) of 2-(4 Methoxy-benzenesulfonyl)5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid was isolated as semi-solid by following the procedure as outlined in example 9. MS: 518.6 (M+H)⁺.

[0240] Starting from 2-(4-Methoxy-benzenesulfonyl)5-mnethyl-2-[4-(2-morpholin~ylethoxy) benzyl]-hex4inoic acid (1.0 g, 1.9 mmol) and following the procedure as outlined in example 1, 450 mag of 2-(4-Methoxy-benzenesulfonyl)5-methyl-2-[4-(2-morpholinyl-ethoxy)benzyl]-hexAenoic acid hydroxyamide was isolated as pale yellow solid. Yield: 450 mg, 45%; mp 92° C. (HCI Salt); MS: 570 (M+H)⁺; ¹H NMR (300 MHz, CDCI₃): 5 1.3 (d, 3H), 1.65 (d, 2H), 3.5 - 1.8 (m, 14 H), 3.9 (s, 3H), 4.5 (in, 2H), 5.4 (m, 1), 6.5 - 7.9 (m, 8H), 11.5 (bs, IH).

EXAMPLE 25 N-Hydroxy-2-(4-ethoxy-benzenesulfonyl)2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy) phenyl1-propionamide

[0241] To a stirred solution of 4hydroxy thiophenol (12.6 g, 100 mmol) and triethyl amine (15.0 g, 150 mpnol) in chloroform (400 ml) 2-bromo ethylpropionate (18.2 g, 100 mmol) was added drop wise. The reaction mixture was refluxed for 1 hr and cooled to room temperature. The reaction mixture was washed with water, dried and concentrated. 2-(4-hydroxy-phenylsulfanyl)propionic acid ethyl ester was isolated as colorless oil. Yield: 22.0 g, 99%, MS: 227 (M+H).

[0242] To stired solution of 2-(4hydroxy-phenylsulfanyl)propionic acid ethyl ester (11.3 g, 50 mmol), and K₂CO₃ (50 g, excess) in acetone (300 ml) ethyl iodide (20 ml, excess) was added and refluxed for 8 hrs. At the end, reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform and washed well with water. It was dried and concentrared. The product, 2-(4-ethoxy-phenylsulfanyl)propionic acid ethyl ester was isolated as colorless oil. Yield: 12.0 g, 98%; MS: 255 (M+H). 2-(4-Ethoxy-phenylsulfanyl)propionic acid ethyl ester was converted to 2-(4-ethoxy-2o phenylsulfonyl)propionic acid ethyl ester by following the procedure as described in example 9, paragraph 2.

[0243] Following the procedure as outlined in example 12, 2-(4-etfioxy-benzenesulfonyl)2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy)phenyl]-propionlic acid ethyl ester was prepared, stargin from (3.5 g, 12.2 mmol) of 2-(4-ethoxy-benzenesulfonyl)propioni, acid ethyl ester and the 4 (2-N,N-diethyl arino-ethoxy)benzyl chloride (3.5 g, 12.2 mmol). Yield 4.8 g, 80%; Brown oil; MS: 492.6 (M+H)⁺.

[0244] Starting from 2-(4ethoxy-benzenesulfonyl)2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy) 30 phenyl]-propionic acid ethyl ester (4.0 giM, 8.1 mmol) 3.2 g (Yield: 80%) of 2-(4-ethoxy-benzenesulfonyl)2-methyl-3-[$(2-N,N-diethyl amino-ethoxy)phenyl]-propionic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 464.5 (M+H)⁺.

[0245] Starting from 2-(4-ethoxy-benzenesulfonyl)2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy) phenyl1-propionic acid (2.0 g, 4.3 mmol) and following the procedure as outlined in example 1, 1.2 g of 2-(4ethoxy-benzenesulfonyl)2-methyl-3-[4-( 2-NaN diethyl amnuethoxy) phenyl]-propionamide was isolated as colorless low melting solid. Yield: 1.2 g, 57%; (HCI Salt); MS: 478.5 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 8 0.9 (t, 3H), 1.1 (t, 6H), 1.3 (s,3M), 3.2 - 3.9 (m, 8 H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5 - 7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 26 (4E)2-4-Methoxy-benzenesulfonyl)5,9methyl-2-[(2-morpholinfy1-ethoxy) benzyl]-deca4,8-dienoic acid hydroxyamide

[0246] To a stirred solution of (4-methoxy-benzenesulfonyl)acetic acid ethyl ester (5.16 g, 20 mnmol), geranyl bromide (4.2g, 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2C₀₃ (10 gis, excess) and the mixture refluxed foe 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO₄, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2-(4-methoxy-benzenesulfonyl)5,9-dimethyl-deca-4,8-dienoic acid ethyl ester was isolated as a colourless oil. Yield: 7.0 g, 89%.

[0247] Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[$(2-morpholin4-y1-ethoxy)benzyl]-deca4,8-dienoic acid ethyl ester was prepared, starting from (1.0 g, 2.5 mmol) of 2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-deca4,8-dienoic acid ethyl ester and 4-(2-morpholin-1-y1-ethoxy)benzyl chloride (800 mig, 2.5 mmol). Yield 1.2 g, 76%; Brown oil; MS: 614 (M+H)⁺.

[0248] Starting from 2-(4-Methoxy-benzenesulfonyl)5,9-dimethyl-2-[4-(2-morpholin4y1-ethoxy) benzyl]-deca4,8-dienoic acid ethyl ester (2.0 gin, 3.2 mnmol) 1.5 g (Yield: 80%) of 2-(4 Methoxy-benzenesulfonyl)5,9-dimethyl-2-E(2-morpholin4-y1-ethoxy)benzyl1-deca-4,8-dienoic acid was isolated as semi-solid by following the procedure as outlined in example 9. MS: 586.6 (M+H)⁺.

[0249] Starting from 2-(4-Methoxy-benzenesulfonyl)5,9-dimethyl-2-[4-(2-morpholin4y1-ethoxy) benzyl]-deca4,8-dienoic acid (1.0 g, 1.7 mmol) and following the procedure as outlined in example 1, 550 mg of (4E)2-(4-Methoxy-benzenesulfonyl)5,9-dimethyl-2-[4-(2-morpholin-4y1-ethoxy)benzyl]-deca4,8-dienoic acid hydroxyamide was isolated as pale yellow solid. Yield: 550 mg, 53%; mp 61° C. (HCI Salt); MS: 638 (M+H)⁺.

EXAMPLE 27 2-[4[2-Diethylammoethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)hexanoic acid hydaoxyamide

[0250] 2-[4-(2-Diethylaminoethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)hexanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Stardng from 2-(4-methoxy-benzenesuifonyl)hexanoic acid ethyl ester (4 g, 12.7 mmol) and (2-(4chloromethyl-phenoxy)ethyl]diethylamine (3.38 g, 14 mmol). Yield 8.21 g crude (100%7); brown oil; MS: 520.4 (M+H).

[0251] 2-{(2-Diethylamnmo-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)hexanoic acid was prepared starting from 2-[4-(2diethylaminoethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl) hexanoic acid ethyl ester (8 g, 15.4 mmol) dissolved in methanol (200 ml) and 10 N NaOH (30 ml). The resulting mixture was worked up as outlined in example 1. Yield 3.88 a crude (51%); brown oil; MS: 492 (M+H)⁺.

[0252] Starting from 2-(4-(2-diethylamino-ethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)hexanoic acid (3.88 g, 7.89 miol) and following the procedure as outlined in example 1, 800 mg of 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid hydroxyanmide was isolated as a yellow powder. Yield 20%; mp 67 ° C.; MS: 507.4 (i+H)I+; ¹H NMR (300 MHz, DMSO-d₆): 5 0.75 (t, J=7.1 Hz, 3H), 1.05 (m, 2 H), 1.23 (t, J=7.2 Hz, 6H) 1.37-1.91 (m, 2H), 3.13 (m, 4H), 3.38-3.51 (m, 4H), 3.87 (s, 3H), 4.3 (t, J=4.8 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 7.15 (m, 4H), 7.7 (d, J='9 Hz, 2H), 9.07 (s, IH), 10.1 (s, IH)

EXAMPLE 28 N-Hydroxy-2-(4n-butoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin- 1-yl-ethoxy)phenyl]-propionamide

[0253] Following the procedure as outlined in example 12, 2-(4n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-y1-ethoxy)phenyl]-propionic acid ethyl ester was prepared, starting from (3.1 g, 10 inmol) of 2-(4n-butoxy-benzenesulfonyl)propionic acid ethyl ester (Prepared from 2-(4hydroxy-phenylsulfanyl)propionic acid ethyl ester and n-butylbromide following the procedure outlined in example 27 )the 4-(2-piperidin-1-y1-ethoxy)benzyl chloride (3.0 g, 10.1 mmol). Yield 4.5 g, 84%; Brown oil; MS: 532.7 (M+H)⁺.

[0254] Starting from 2-(4-n-butoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-y1-ethoxy) phenyl1-propionic acid ethyl ester (5.0 gm, 9.4 mmol) 4.2 g (Yield: 88%) of 2-(4-n-butoxy-benzenesulfonyl)2-methyl-3-[4-(²-piperidin-1-y1-ethoxy)phenyl]-propionic acid was isolated as colorless solid by following the procedure as outlined in example 9. MS: 504.6 (M+)⁺

[0255] Starting from 2-(4-n-butoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-y1-ethoxy) phenyl]-propionic acid (3.0 g, 5.9 mmol) and following the procedure as outlined in example 1, 1.3 g of 2-(4-n-butoxy-benzenesulfonyl)2-methyl-3-f4-(2-piperidine-1-y1-ethoxy) phenyl]-propionamide was isolated as colorless solid. MP. 65 C, Yield: 1.3 g, 42%; (HCI Salt); MS: 478.5 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 3 0.9 (t, 3H), 1.2 (s, 3H), 1.3 - 1.9 (m,10H), 2.8 - 4.5 (m, 12 H), 6.8 - 7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 29 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-Nethyl amino-ethoxy) phenyl]-propionamide

[0256] Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2-methyl-20 3-[3-(2-N,N-diethyl amino-ethoxy)phenyl]-propionic acid ethyl ester was prepared, starting from (5.0 g, 18 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and the 3-(2-N,N-diethyl anino-ethoxy)benzyl chloride (4.9 g, 18 mrol). Yield 8.1 g, 93%; Brown oil; MS: 478.1 (M+H)⁺.

[0257] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-N,N-diethyl amino-ethoxy) phenyl1-propionic acid ethyl ester (8.1 gm, 16.9 rnmol) 6.7 g(Yaield: 88%) of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-N,N-diethyl amino-ethoxy)phenyl]-propionic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MP: 78-81; MS: 450.1 (M+H)⁺.

[0258] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-N,N-diethyl amino-ethoxy) phenyl]-propionic acid (6.7 g, 15 mmol) and following the procedure as outlined in example 1, 1.5 g of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-N,N-diethyl amino-ethoxy) phenyl]-propionamide was isolated as colorless low melting solid. Yield: 1.5 g, 21%; (HCI 35 Salt); MS: 450.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 3 1.21 (t, 6H), 1.26 (s, 3H), 3.18-3.24 (m, 2H), 3.38 (m, 4U), 3.43-3.46 (m, 2H), 3.80 (s, 3H), 4.30 (s,2H), 6.76-6.78 (d, 2H), 6.84-7.2 (m,6H), 10.3 (bs, 1H).

EXAMPLE 30 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-morpholin- 1 -y1-ethoxy) phenyl]-propionamide

[0259] Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yi-ethoxy)phenyl1-propionic acid ethyl ester was prepared, starting from (5.2 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and the 3-2-morpholin-1-y1-ethoxy)benzyl chloride (6.0 g, 20 mmol). Yield 9.1 g, 93%; Brown oil; MS: 492 (M+H)⁺.

[0260] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-morpholin-1-y1-ethoxy) phenyl]-propionic acid ethyl ester (10.0 g 20.3 mmol) 8.0 g (Yield: 86%) of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-f3-(2-morpholin-1-y1-ethoxy)phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9.; MS: 464.5 (M+H)⁺.

[0261] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-morpholin-1-y1-ethoxy) phenyl]-propionic acid (4.55 g, 9.8 mmol) and following the procedure as outlined in example 1, 440 mg of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[3-(2-morpholi- 1-y1-ethoxy) phenyl]-propionamide was isolated as colorless solid. Yield: 440 mg, 9%; mp 63° C.; MS: 479.5 (M+H)⁺; ¹H NMR (300 Mhz, DMSO-d6): 8 1.26 (s,'3H), 3.18- 3.8 (m, 12H), 3.9 (s, 3H), 4.4 (m, 2H), 6.7 - 8.8 (m, 8H), 10.8 (bs, IH).

EXAMPLE 31 6-(1 ,3-Dioxo- 1 ,3-dihydro-isoindo1-2-yl)2-(4medioxy-benzenesulfonyl)-2-methyl hexanoic acid hydroxyamide

[0262] Following the procedure as outlined in Example 9, 6-(l,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)2-methyl-hexanoic acid ethyl ester was prepared, staring from (5.0 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and 4-phathalimido bromobutane (5.66 g, 20 mmol). Yield 8.4 g, 97%; Colorless oil; MS: 474 (M+H).

[0263] Starting from 6-(1,3-Dioxo-1,3-dlhydro-isoindol-2-yl)2-(metoxy-benzenesulfonyl)-2-methyl-hexanoic acid ethyl ester (8.4 g, 17.7 mmol) 6.95 g (88%) of 6-(l,3-Dioxo-1,3-dihydro-isoindol-2-yl)2-(4-methoxy-benzenesulfonyl)2-methyl-hexanoic acid was isolated as colorless oil by following the procedure as outlined in Example 9. MS: 446 (M−H).

[0264] Starting from 6-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid (4.9 g, 1-1 rnmol) and following the procedure as outlined in Example 1, 3.1 g of 6(1,3-Dioxo-1,34hydro-isoindol-2-yl)2-(4-methoxy-benzenesulfonyl)2-methyl hexanoic acid hydroxyamide was isolated as a light brown solid; Yield: 46%; mp 146 148 ° C.; MS: 461.2 (M+H)⁺; ¹H NMR (300 A, DMSOd4): 5 1.55 (s, 3H), 1.61- 3.77 (m, 8H), 3.82 (s, 3H), 6.92-8.21 (m, 8H), 10.70 (bs,IH), 11.20 (bs,IH).

EXAMPLE 32 3-[>(2-Diethylamino-ethoxy)phenyl1-2(furan-2-y1-benzenesulfonyl)N-hydroxy-2-methyl-propionamide

[0265] To a stirred solution of 4-bromo thiophenol (19.0 g, 100 mmol) and triethyl amine (15.0 g, 150 mmol) in chloroform (400 ml1) 2-bromo ethylpropionate (18. 2 g, 100 mnmol) was added drop wise. The reaction mixture was refluxed for 1 hr and cooled to room temperature. The reaction mixture was washed with water, dried and concentrated. 2-(4bromo-phenylsulfanyl) propionic acid ethyl ester was isolated as colorless oil. Yield: 28.0 g, 99%, MS: 290 (M+H). 2-(4bromo-phenylsulfanyl)propionic acid ethyl ester was converted to 2-(4-bromo-phenylsulfonyl)propionic acid ethyl ester by following the procedure as described in example 9, paragraph 2.

[0266] A mixture of 2-(4-bromo-phenylsulfonyl)propionic acid ethyl ester (6:4 g, 20 rhmol), 2-(tributyl stannyl)firan (7.5g, 21 mmol) and (Ph₃P)4Pd (500 mg) was refluxed in degassed tolune (250 ml) for 8 hrs. At the end reaction mixture was filtered through Celite and concentrated. The product was purified by silica gel column chromatography by eluting it with 50% ethylacetate: hexane. Colorless oil. Yield: 5.9 g, 95%, MS: 309 (M+H).

[0267] Following the procedure as outlined in example 12, 2-(4-(2-furany1-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy)phenyl]-propionic acid ethyl ester was prepared, starting from (3.08 g, 10.0 nmmol) of 2-(4-(2-fiarany1-benzenesulfonyl)propionic acid ethyl ester and the 4-(2-N,N-diethyl -amino-ethoxy)benzyl chloride (3.5 g, 12.2 mmol). Yield 5.0 g, 97%; Brown oil; MS: 514.6 (M+H)⁺.

[0268] Startng from 2-4-(2-f y1-benzenes ulfonyl)2-methyl-3-[4-(2-N,N ethyl amino-ethoxy) phenyl]-propionic acid ethyl ester (5.1 gm, 10.0 mmol) 3.8 g (Yield: 78%) of 2-(4-(2-faronyl-benzenesulfonyl)2-methyl-3-R-(2-N, ethyl amino-ethoxy)phenyl]-propionic acid was isolated as colorless solid by following the procedure as outlined in example 9. MP: 58 C, MS: 486.5 (M+H)⁺.

[0269] Startng from 2(4-(2-y1-benzenesulfonyl)2-methyl-3->(2-N2Nethyl amionethoxy) phenyl]-propionic acid (5.0 g, 10.3 mmol) and following the procedure as outlined in example 1, 1.2 g of 2-(4ethoxy-benzenesulfonyl)2-methyl-3-[4-(2-N,N-diethyl aminoethoxy) phenyl]-propionamide was isolated as colorless low melting solid Yield: 3.2 g, 62%; (HCI Salt); MS: 502 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 5 1.23 (t, 6H), 1.4 (s, 2H), 2.8 (q,4H), 3.0 (t, 2 H), 4.1 (t, 2H), 6.5 - 8.0 (m, 7H).

EXAMPLE 33 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-[4-(2-morpholinyl-ethoxy)benzyl]-butyramide

[0270] 2-(4-Methoxy-phenylsulfanyl)butyric acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g, 50 mmol), 5.19 g (40%); clear oil; MS: 255.2 (iM+H)⁺. 2-(4-Methoxy-benzenesulfonyl)butyric acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(4-methoxy~phenyisulfanyl)butyric acid ethyl ester (5 g, 20 rnmol). Yield 5.74 g (100%); clear oil; MS: 287.1 (M+H)M.

[0271] Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl)2-[>(2-morpholinlyl-ethoxy)benzyl]-butyric acid ethyl ester was prepared, starting from (3.5 g, 12.2 mmol) of 2-(4-methoxy-benzenesulfonyl)butric acid ethyl ester and the 4-[2-(chloromethyl-phenoxy)ethyl]-morpholine (2.34 g, 6.7 mmol). Yield 5.7 g, 100%; Brown oil; MS: 506.4 (M+H)⁺.

[0272] Starting from 2-(4-Methoxy-benzenesulfonyl)2-[4-(2-morpholinyl-ethoxy)benzyl]-butyric acid ethyl ester (5.54 gm, 1 -1 mmol) 2.9 g (Yield: 55%) of 2-(4-Methoxy-benzenesulfonyl)2-[42-morpholinyl-ethoxy)benzyl]-butyric acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 478.3 (M+H)⁺.

[0273] Starting from 2-(4methox-benzenesufonyl)2-[(2-morpholin~yl-ethoxy)benzya g-butyric acid (2.6′g, 5.4 mmol) and following the procedure as outlined in example 1, 510 mg of N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-(42-morpholinyl-ethoxy)benzyl]-butyramide was isolated as a brown solid. Yield 2%; mp 51 ° C.; MS: 493.3 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): 8 0.90 (t, J=7.2 Hz, 3H), 1.69-1.96 (m, 4 H), 2.67 (t, 2H), 3.34 (m, 8H), 3.87 (s, 3H), 4.04 (m, 2H) 6.8 (d, J=8.7 Hz, 2H), 7.14 (m, 4H), 7.73 (d, J=4.7 Hz, 2H), 9.08 (s, 1H), 10.8 (s, 1H).

EXAMPLE 34 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-[4-(2-piperidin-1-yl-ethoxy)benzyl]-butyramide

[0274] Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl)2-[>(2-piperidin-1-yl-ethoxy)benzyl]-butync acid ethyl ester was prepared, starting from (1.0 g, 3.33 mmol) of 2-(4-methoxy-benzenesulfonyl)butyric acid ethyl ester and the 1-[2-(4 chloromethyl-phenoxy)ethyl]-piperidine (0.85 g, 3.36 mmol). Yield 1.07 g, 62%; Brown oil; MS: 504.4 (M+H)⁺.

[0275] Starting from 2-(4-Methoxy-benzenesulfonyl)2-[4-(2-pipe,ridin-1-yl- ethoxy)benzyl]-butyric acid ethyl ester (3.7 gm, 7.3 mmol) 22 g (Yield: 63%) of 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl- ethoxy)benzyl]-butync acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 476 (M+H)⁺.

[0276] Starting from 2-(4-Methoxy-benzenesulfonyl)2-[4-(2-piperidin- 1 -yl- ethoxy)benzyl]-butyric acid (2.2 g, 4.63 mmol) and following the procedure as outlined in example 1, 360 mg of N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-[4-(2-piperidin- 1 -yl-ethoxy)benzyl]-buy de was isolated as a brown solid. Yield 16%; mp 75 ° C.; MS: 491.3 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 0.90 (t, J=7.1 Hz, 3H), 1.36-1.96 (m, 4 H), 2.4-2.63 (m, 14H), 3.87 (s, 3H), 4.01 (t, 3 =5.9 Hz, 2H) 6.8 (d, J=8.5 Hz, 2H), 7.11 (m, 4H), 7.71 (d, J=8.8 Hz, 2H), 9.09 (s, 1H), 10.8 (s, 1H)

EXAMPLE 35 2-a4-Methoxy-benzenesulfonyl)2-[4-(2-morpholin~yl-ethoxy)benzyl1-pentanoic acid hydroxyamide

[0277] 2-(4-Methoxy-phenylsulfanyl)pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromovalerate (8.23 g, 39.3 mmol) and 4-methoxythiophenol (5 g, 35.7 mmol), 10.46 g (100%); clear oil; MS: 269 (M+')⁺.

[0278] 2-(4-Methoxy-benzenesulfonyl)pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(4-methoxy-phenylsulfanyl) pentanoic acid ethyl ester (6.9 g, 27.4 mmol). Yield 7.07 g (86%); clear oil; MS: 300.9 (M+H)⁺.

[0279] Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl)2-f(2-morpholintyl-ethoxy)benzyl]-pentanoic acid ethyl ester was prepared, starting from (3.0 g, 10.8 mmol) of 2-(4-methoxy-benzenesulfonyl)pentanoic acid ethyl ester and the 4-[2-(chloromethyl-phenoxy)ethyl1-morpholine (3.45 g, 11.9 m=ol). Yield 3.08 g, 62%; Brown oil; MS: 520.4 (M+H)⁺.

[0280] Starting from 2-(4-Methoxy-benzenesulfonyl)2-[4-(2-morpholintyl-ethoxy)benzyl]-pentanoic acid ethyl ester (2.73 gm, 5.27 mmol) 1.45 g (Yield: 56%) of 2-(4-Methoxy-benzenesulfonyl)2-[4-(2-morpholinfylethoxy)benzyl]-pentanoic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 492.3 (M+H)⁺.

[0281] Starting from 2-(4-methoxy-benzenesulfonyl)2-[4-(2-morpholin yl-ethoxy)benzyl]-pentanoic acid (1.01 g, 2.05 mmol) and following the procedure as outlined in example 1, 190 mg of 2-(4-methoxy-benzenesulfonyl)2-(4-(2-uiorpholin-4yl-ethoxy)benzyl]-pentanoic acid hydroxyamide was isolated as abrown solid. Yield 18%; mp IO1 ° C.; MS: 507.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): 5 0.71 (t, J=7 Hz, 3H), 1.58-1.82 (m, 4 H), 3.12-3.98 (m, 12H), 3.87 (s, 3H), 4.35 (t, 2H) 6.89 (d, J=8.7 Hz, 2H), 7.15 (m, 4H), 7.74 (d, J=8.9 Hz, 2H), 9.08 (s, 1H).

EXAMPLE 36 2-[>(2-Azepan-1-yl-ethoxy)benzyl]-2-(4-Methoxy-benzenesulfonyl)octanoic acid hydroxyamide

[0282] 2-(4-Methoxy-phenylsulfanyl)octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (+H)⁺, 2-(4-Methoxy-benzenesulfonyl)ctanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ²-(4-methoxy-phenylsulfanyl)octanoic acid ethyl ester (4.0 g, 13.6 mmol). Yield 3.7 g (83%); clear oil; MS: 343.3 (M+H)⁺.

[0283] Following the procedure as outlined in example 12, 2-[W(2-Azepan-1-yl-ethoxy)benzyl]-2-(4-Methoxy-benzenesulfonyl)octanoic acid ethyl ester was prepared, starting from (1.69 g, 5.18 mmol) of 2-(4-methoxy-benzenesulfonyl)octanoic acid ethyl ester and the 1-[2-(4 chloromethyl-phenoxy)ethyl]-azepane (1.73 g, 6.0 mmol). Yield 4.86 g, 99%; Brown oil; MS: 574.5 (M+Hl)⁺.

[0284] Starting from 2-[4-(2-Azepan-1-yl-ethoxy)benzyl]-2-(4-Methoxy-benzenesulfonyl)octanoic acid ethyl ester (4.8 gm, 8.37 mmol) 1.55 g (Yield: 34%) of 2-[4-(2-Azepan-1-ylethoxy) benzyl]-2-(4-Methoxy-benzenesulfonyl)octanoic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 551 (M+H)⁺.

[0285] Starting from 2-[4-(2-Azepan- 1-yl-ethoxy)benzyl]-2-(4-Methoxy-benzenesulfonyl)octanoic acid (1.09 g, 2.0 mmol) and following the procedure as outlined in example 1, 300 mg of 2-[4-(2-Azepan-1-yl-ethoxy)benzyl]-2-(4-Methoxy-benzenesulfonyl)octanoic acid hydroxyamide was isolated as a yellow solid. Yield 27%; mp 65 ° C.; MS: 561.6 (M+H)⁺; ¹H N,NIR (300 MHz, DMSO-d₆): 5 0.81 (t, 3 =6.6 Hz, 3H), 1.08-1.82 (m,14H), 3.13-3.51 (m, 12H), 3.87 (s, 3H), 4.33 (t, 2H) 6.88 (d, J=8.7 Hz, 2H),7.14 (m,4H), 7.7 (d, 3=9Hz, 2H), 9.06 (s, 1H), 10.28 (s, 1H).

EXAMPLE 37 2-(4-Methoxy-benzenesulfanyl)octancic acid hydroxyamide

[0286] 2-4-Methoxy-phenylsulfanyl)octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 inmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H)⁺.

[0287] Starting from 2-(4-Methoxy-benzenesulfanyl)mtanoic acid ethyl ester (3.1 gm, 10 mmol) 255 g (Yield: 90%) of 2-(4-Methoxy-benzenesulfanyl)octanoic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 283 (M+H)⁺.

[0288] Starting from 2-(4-Methoxy-benzenesulfanyl)octanoic acid (4.25 g, 16 mmol) and following the procedure as outlined in example 1, 3.64 g of 2-(4-Methoxy-benzenesulfanyl)octanoic acid hydroxyamide was isolated as colorless solid. Yield: 76%, NP: 90 C; MS: 298.2 (M+H).

EXAMPLE 38 2-(4-Fluorophenylsulfanyl)octanoic acid hydroxyamide

[0289] 2-(4-Fluoro-phenylsulfanyl)octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (6.47 g, 24.7 mnmol) and 4-fluorothiophenol (3 g, 23.4 mmol). Yield: 6.31 g (9,0%); clear oil; MS: 299 (M+H)⁺.

[0290] Starting from 2-(fluoro-benzenesulfanyl)octanoic acid ethyl ester (3.1 gm, 10 miol) 2.89 g (Yield: 100%) of 2-(4-fluoro-benzenesulfanyl)octanoic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 268.9 (M+H)⁺.

[0291] Starting from 2(4-fluoro-benzenesulfanyl)octanoic acid (2.49 g, 9.2 mmol) and following the procedure as outlined in example 1, 2.72 g of 2-(4-fluoro-benzenesulfanyl)octanoic acid hydroxyamide was isolated as colorless solid. Yield: 99%, MP: 58 C; MS: 284(M−H).

EXAMPLE 39 2(-methy-lHimidazo1-2-yl anyl)Octanoic acid hydroxyamide

[0292] 2(-methyl-lH-imidazo1-2-ylsulfanyl)octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Stardtng from ethyl 2-bromooctanoate (12.1 g, 48 mmol) and 1-methyl-2-mercapto imidazole (5 g, 43.8 mnmol). Yield: 12 g (96%); clear oil;

[0293] MS: 285 (M+H)⁺.

[0294] Starting from 2-(I-methyl-1H-imidazo1-2-ylsulfanyl)ctanoic acid ethyl ester (12 gm, 422 mmol) 10.2 g (Yield: 95%) of 2-(1-methyl-1H-imidazo1-2-ylsulfanyl)octanoic acid was isolated as colorless solid by following the procedure as outlined in example 9. MP: 95 C, MS: 257.1 (M+H)⁺.

[0295] Starting from 2-(I-methyl-1H-imidazo1-2-ylsulfanyl)octanoic acid (7.84 g, 30.6 mmol) and following the procedure as outlined in example 1, 2.77 g of 2-(1-methyl-1H-imidazo1-2-yl-sulfanyl)octanoic acid hydroxyamide was isolated as colorless solid. Yield: 33%, MP: 125 C; MS: 272.2 (M+H).

EXAMPLE 40 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)3-naphthalen-2-yl-propionamide

[0296] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzensulfonyl)-3-naphthalen-2-yl-propionic acid ethyl ester was prepared, starting from (5.0 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and 2-bromomethyl naphthalene (4.4 g, 20 mmol). Yield 7.2 g, 91%; Colorless oil; MS: 399 (M+H)⁺.

[0297] Starting from 2-(4-methoxy-benzenesulfonyl)3-naphthalen-2-yl-propionoic acid ethyl ester (3.7 g, 9 mmol) 3.3g (96%) of 2-(4-methoxy-benzenesulfonyl)3-naphthalen-2-yl-propionoic acid was isolated as colorless oil by following the procedure as outlined in Example 9. MS: 369.1 (M−H).

[0298] Starting from 2-(4-methoxy-benzenesulfonyl)3-naphthalen-2-yl-propionic acid (2.2 g, 5.9 mmol) and following the procedure as outlined in Example 1, 820 mg of N-hydroxy-2(4 methoxy-benzenesulfonyl)3-naphthalen-2-yl-propionaride was isolated as a light brown solid; Yield: 36%; mp 161- 163 ° C.; MS: 385.9 (M+I)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 8 3.32 (d, J=7.0 Hz, 1H), 3.69 (d, J=7.0 Hz, 1H), 3.82 (s, 3H), 5.02 (s, 1H), 6.92-7.89 (n, 1 H).

EXAMPLE 41 N-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)2-methyl-3-phenyl propionic acid hydroxamide

[0299] A mixture of 4-methoxybenzyl mercaptan ( 7.Og, 45 mmol), ethyl 2-bromopropionate (8.2 g, 46 mmol) and powdered oven dried potassium carbonate ( lOg, 72 mmol) in 150 mL of acetone was heated at reflux for 18 h. The mixture was cooled, filtered, and the filtrate concentrated. The residue was taken up in 150 mL of methylene chloride, washed with water (150 mL), dried over anhydrous sodium sulfate and evaporated to yield 12 g (99%); colorless liquid; MS 255.1 (M+H). This product is used without further purification.

[0300] To an ice cold (5 ° C.) solution of 2-(4-methoxy-phenylmethanesulfanyl)propionic acid ethyl ester (5.7g, 21 mmol) in 100 mnL CH₂C₁₂ was added portionwise (7.2g, 40 m=nol) of m-chloroperbenzoic acid and the mixture was stirred for 1 h. The reaction was diluted with hexanes (500 mL) and stirred at 25 C'for 30 minute at room temperature. The mixture was filtered and the organic layer treated with saturated aqueous sodium bisulfite (200 mrL). The hexanes solution containing the product was washed with water, dried (Na2SO4) and concentrated. Yield 5.5g (91%); colorless oil; MS 287.1 (M+H)'.

[0301] Following the procedure as outlined in Example 9, 2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester was prepared, starting from 2-(4-Methoxy-phenylmethanesulfonyl)propionic acid ethyl ester (2g, 7 mmol) and benzyl bromide (1.3g, 7.7 mmol). Yield 3.0 e, 100%; Low melting solid; MS: 377 (M+H)⁺.

[0302] 2-(4-Methoxy-phenylmethanesulfonyl)2-methyl-3-phenyl-propionic acid was prepared starting from 2-(4-Methoxy-phenylmethanesulfonyl)2-methyl-3-phenyl-propionic acid ethyl ester (3.5 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH. (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 930 mg, 31%. Colorless solid, mp: 106-108 C;. MS: 347 (M−H)⁺.

[0303] Starting from 2-(4-Methoxy-phenylmethanesulfonyl)2-methyl-3-phenyl-propionic acid (2.7 g, 7.0 mmol) and following the procedure as outlined in example 1, 266 mg of N-Hydroxy-2-(4 methoxy-phenylmethanesulfonyl)2-methyl-3-phenyl propionic acid hydroxamide was isolated as light colorless solid; Yield. 10%; mp 58-59 ° C.; MS: 364.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 3 1.28 (s, 3H), 2.842.88 (d, 1H), 3.75 (s, 3H), 3.81-3.86 (d, 1H), 4.594.63 (d, 1H), 4.694.74 (d, 1H), 6.94-6.98 (d, 2H), 7.19 (m, 2H), 7.29-7.33 (d, 4H), 9.24 (s, 1H), 10.88 (s, 1H).

EXAMPLE 42 5-Methyl-2-(3-methyl-but-2-enyl)2-(toluene4sulfonyl)hex~enoic acid hydroxyamide

[0304] 5-Methyl-2-(3-methyl-but-2eny)2-(toluene~sulfonyl-hextenoic acid ethyl ester was prepared according to general method as outlined in example 9. Starting from ethyl c-(p-tolylsulfonyl)acetate (2.9g, 10.9 nmmol and 4-bromo-2-methyl butene (3.42g, 23 mmol). Yield 4.6g; tan oil; MS 379.2 (M+H)⁺. 5-methyl-2-(3-methyl-but-2enyl)2-(toluene~sulfonyl)hex4 oic acid was prepared according to general method as outlined in example 9. Startig from 5-methyl-2-(3-methyl-but-2-enyl)2-(toluene4sulfonyl-hexfnoic acid ethyl ester (4.5g, 11 mmol), ethanol (15 mL) and 10-N sodium hydroxide.

[0305] Starting from 5-methyl-2-(3-methyl-but-2enyl)2-(toluene~sulfonyl)hexenoic acid (4.1 g, 11 mmol) and following the procedure as outlined in example 1, 1.07 g of 5-Methyl-2-(3-methyl-but-2-enyl)2-(toluene~sulfonyl)hex-4-enoic acid hydroxyamide was isolated as colorless solid; Yield: 30%; mp 108-1 10 ° C.; MS: 366.2 (M+H)⁺; ¹H NMR (300 M~z, DMSO-d₆:51.49 (s, 6H), 1.62 (s, 6H), 2.41 (s, 3H), 2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H), 7.40-7.43 (d, 2H), 7.59-7.62 (d, 2H), 9.04 (s, 1H), 10.80 (s, 1H).

EXAMPLE 43 2-Methyl-2-(2-methyl-furan-3-sulfonyl)3-phenyl-propionic acid hydroxamide

[0306] 2-Methyl-2-2-methyl-faan-3-sulfonyl)3-phenyl-propionic acid ethyl ester (Prepared from 3-mercapto-2-methylfiiran) was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-fiuran-3-ylsulfanyl)propionic acid ethyl ester (2.9g, 11.9 mmol), benzyl bromide (2.22g, 13 mmol) and potassium carbonate (log) in acetone (75 IiL). Yield (99%); amber oil; MS 337.1 (M+H)⁺.

[0307] 2-Methyl-2-(2-methyl- n-3-sulfonyl)3-phenyl-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-fiiran-3-ylsulfanyl) propionic acid ethyl ester (4.8g, 14.3 mmol), dissolved in ethanol (25 mL and 10 N sodium hydroxide (10 mL). Yield 3.7g (84%), white solid, MS 307.4 (MI-H).

[0308] Starting from 2-Methyl-2-(2-methyl-furan-3-sulfonyl)3-phenyl-propionic acid (3.58 g, 12 mmol) and following the procedure as outlined in example 1, 1.078 g of 2-Methyl-2-(2-methyl-furan-3-sulfonyl)3-phenyl-propionic acid hydroxyamide was isolated as orange color solid; Yield: 29%; mp 68-70 ° C.; MS: 324 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 1.27 (s, 3H), 2.81-2.86 (d, 1H), 3.33 (s, 3H), 3.61-3.66 (d, 1H), 6.66 (s, 1H), 7.19-7.25 (m, 5H), 7.76 (s, 1H), 9.09 (s, 1H), 10.81 (s, 1H)

EXAMPLE 44 2-Methyl-2-(2-methyl-furan-3-sulfonyl)3-[4-(2-piperidin-1-yl-ethoxy)phenyl]-propionic acid hydroxamide

[0309] 2-Methyl-2-(2-methyl-faran-3-sulfonyl)3-[(2-piperidin-yl-ethoxy)phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-faran-3-sulfonyl)propionic acid ethyl ester (2.4g, 9.8 nmuol) and 1-[2-(4-chloromethylphenoxy)ethyl]-piperidine (2.96g, 10.7 mmol); Yield 2.4g (92%); amber oil; MS 464.2 (M+)⁺.

[0310] 2-Methyl-2-(2-methyl-furan-3-sulfonyl)3-[(2-piperidin-1-yl-ethoxy)phenyl]-propionic acid was prepared according to the general method as outlined in example 1. Starting from 2-methyl-2-(2-methyl-f=ran-3-sulfonyl)3-[(2-piperidin-1-yl-ethoxy)phenyl]-propionic acid ethyl ester (2.01 g, 4.5 mmol), dissolved in ethanol (20 mL) and 10 N sodium hydroxide (10 mLi.). The resulting mixture was worked up as outline in example 9. Yield 2.03g; amber crystals mp 66-68 ° C.; MS 434 (M−H).

[0311] Starting from 2-Methyl-2-(2-methyl-fum-3-sulfonyl)3-[4-(2-piperidin-1-yl-ethoxy)-pheny-]-propionic acid (2.03 g, 6.0 mmol) and following the procedure as outlined in example 1, 1.36 g of 2-Methyl-2-(2-methyl-furan-3-sulfonyl)3-[4-(2-piperdin-1-yl-ethoxy)-phenyl]-propionic acid hydroxyamide was isolated as amber color solid; Yield 32%; mp 115-117 ° C.; MS: 451.1 (M+H)⁺; ¹H NMR (300 MB, DMSO-d6): 5 1.15-1.22 (m, 2H), (1.75 (s, 3H), 1.78 (s, 3m) 2.98-3.03 (m, 2H), 3.42-3.47 (m, 2H), 3.5 (s, 3H), 6.65 (s, 1X), 6.87-6.90 (d, 2H), 7.12-7.17 (d, 2H), 10.35 (s, 1H), 10.60 (s, 1II), 11.70 (s, 1H).

EXAMPLE 45 2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxamide

[0312] 2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared acording to the general method as outlined in example 9. Starting from 2-(thiophene-2-sulfonyl)propionic acid ethyl ester( prepared from 2-mercaptothiophene and 2-bromopropionic acid ethylester) (4.4g, 17.7 mnmol) and 1-[2-(4-chloromethylphenoxy)ethyl]-piperidine (5.3g, 19.5 mmol); Yield (96%); semi-solid; MS 466. 2-Methyl-3-(4-(2-piperidin- 1-yl-ethoxy)phenyl-2-(thiophene-2-sulfonyl)propionic acid was prepared acording to the general method as outlined in example 9. Starting from 2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-sulfonyl)propionic acid ethyl ester (9.8g, 20 mmol), dissolved in ethanol (20 mL) and 10 N sodium hydroxide (20 mii). The resulting mixture was worked up as outline in example 1. Yield 4.5g (49%); white solid mp 170-172 ° C.; MS 436.3 (M−H).

[0313] Starting from 2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)phenyl-2-(thiophene-2-sulfonyl) propionic acid (3.6 g, 8.0 mmol) and following the procedure as outlined in example 1, 345 mg of 2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)phenyl-2-(thiophene-2-sulfonyl)propionic acid hydroxyamide was isolated as light colorless solid; Yield: 10%; mp 115-118 ° C.; MS: 451.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d,): 31.29 (s, 3H), 1.66-1.78 (m, 6H), 2.81-2.86 (d, 1H), 2.96-3.99 (m, 4H), 3.39-3.47 (m, 2H), 3.51-3.59 (d, 1H), 4.32 (ma, 2H),6.72-6.74 (d 1H), 6.87-6.96 (d, 2H), 7.01-7.20 (m, 3H), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 1H), 7.83-7.84 (m, 1H), 8.07-8.08 (dd, 1H), 8.17 (dd, 1H), 9.0 (s, 1H) 10.0 (s, 1H), 10.78 (s, 1H).

EXAMPLE 46 2-(octane-1-sulfonyl)3-[4-(2-piperidin-yl-ethoxy)phenyl]-propionic acid hydroxamide

[0314] 2-(Octane-1-sulfonyl)3-{4-(2-piperidin-ylthoxy)phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(octane-1-sulfonyl)propionic acid ethyl ester (5.0g, 18 mmol) and I-[2-(4chloromethylphenoxy)ethyl]-piperidine (5.6g, 19.7 mmol); Yield 8.9g (96%); amber oil, MS 495. 2-(Octane-1-sulfonyl)3-[4-(2-piperidin-yl-ethoxy)phenyl]-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-(octane-1-sulfonyl) 3-[4-(2-piperidin-yl-ethoxy)phenyl]-propionic acid ethyl ester (8.9g, 18 mmol), ethanol (25 rL) and 10 N sodium hydroxide (25 mL). Yield 6.Og (72%).

[0315] Starting from 2-(Octane-1-sulfonyl)3-[4-(2-piperidin-yl-ethoxy)phenyl]-propionic acid (3.6 g, 7.7 mmol) and following the procedure as outlined in example 1, 3.3 g of 2-(Octane-1-sulfonyl)3-[4-(2-piperidin-yl-ethoxy)phenyl]-propionic acid hydroxyamide was isolated as tan solid; Yield: 89%; mp 69-70 ° C.; MS: 483.2 (M+H)⁺; ¹H NMR (300 -1Hz, DMSO-d₆: δ 0.687 (t, 3H), 1.27-1.69 (m, 15H), 2.71-2.75 (d, 1H), 3.51 (s, 3H), 3.65-3.69 (d, 1H), 6.86-6.89 (d, 2H), 7.08-7.11 (d, 2H), 9.16 (s, 1H), 10.70 (s, 1H).

EXAMPLE 47 3-Biphenyl4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)propionic acid hydroxyamide

[0316] 3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-methyl-(1-methyl-1H-imidazolesulfonyl)propionic acid ethyl ester Prepared from (1-Methyl-2-mercapto imidazole and 2-bromo ethyl propionate) (3.0g, 12.2 mmol) and 4 chIoromethylbiphenyl (2.97g, 15 mmol). Yield 5.Og (99%); low melting solid; MS 413 (M+H)⁺.

[0317] 3-Biphenylyl-2-methyl-2-1-(1methyl-lH-imidazole-2-sulfonyl)propionic acid was prepared according to the general method as outlined in example 9. Starting from 3-biphenylyl-2-methyl2-(I-methyl-1H-imidazole-2-sulfonyl)propionic acid ethyl ester (5.0g, 11.9 mmnol), ethanol (15 mL) and 10 N sodium hydroxide (10 mL). Yield 2.8g (61%); brown solid mp 119-122 ° C.; MS 385.2 (M+H).

[0318] Starting from 3-Biphenylfyl-2-methyl-2-(1-methyl-lH-imidazole-2-sulfonyl)propionic acid (2.8 g, 7.0 mmol) and following the procedure as outlined in example 1, 112 mg of 3-Biphenyl-4yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)propionic acid hydroxyamide was isolated as tan colored solid; Yield: 4%; mp 112 ° C.; MS: 399.0 (M+HI)⁺; ¹H NMR (300 MHz, DMSO-d₆): 8 0.911 (s, 3H), 3.3 (s, 3H), 3.5 (d, 1H), 4.2 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.18-7.66 (m, 5H), 7.30-7.33 (d, 2H), 7.55-7.58 (d, 2H).

EXAMPLE 48 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)propionic acid hydroxamide

[0319] 2-Methyl-3-phenyl-2-(tiophene-2-sulfonyl)propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(thiophen-2-sulfonyl) propionic acid ethyl ester (3.0g, 12 mmol) and benzyl bromide (2.48g, 15 mmol). Yield 5.2 g (%); tan oil; MS 339.1 (M+H).

[0320] 2-Methyl-3-phenyl-2-(thiophene2-sulfonyl)propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-methyl-3;phenyl-2-(thiophen-2-sulfonyl)propionic acid ethyl ester (5.0 g, 15 mmol), ethanol (30 mL) and 10 N sodium hydroxide (10 mL). Yield 5.6g MS 310.0 (M+H).

[0321] Starting from 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)propionic acid (5.0 g, 16 mnmol) and following the procedure as outlined in example 1, 1.8 g of 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)propionic acid hydroxyamide was isolated as colorless solid; Yield: 40%; mp 116-117 ° C.; MS: 325.9 (M+H)⁺; ¹H NVIR (300 MHz, DMSO-d₆): 5 1.29 (s, 3H), 3.33 (d, lH), 3.69 (d 1H), 7.18-7.30 (m, 5H), 7.74 (m, 1H), 8.22 (m, 1H), 9.13 (s, 1H), 10.80 (s, 1H).

EXAMPLE 49 2-(8-(1-carboxy-ethanesulfonyl)octane-1-sulfonyl1-propionic acid hydroxyamide

[0322] 2-[8-1-Carboxyl-ethanesuifonyl)octane-1-sulfonyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-[8-(1-ethoxycarbonyl-ethylsulfanyl)Ictylsulfanyl]-propionic acid ethyl ester (10.2g, 26 mmol) and sodium peroxymonopersulfate (64;, 104 mmol). Yield 9.87g (86%); colorless liquid; MS 442.9 (M+H).

[0323] 2-[8l -Carboxy-ethanesulfonyl)octane- 1-sulfonyl]-propionic acid was prepared according to general method as outline in example 1. Starting from 2-[8-(1-carboxy-ethanesulfonyl)octane-1-sulfonyl]-propionic acid ethyl ester (3.Og, 6.8 mmol), ethanol (15 mL) and 10 N sodium hydroxide (15 mL). Yield 2.7g (98%); white solid mp 99-102 ° C.; MS 387 (M+NH3)⁺.

[0324] Starting from 2-[8-(1-Carboxy-ethanesulfonyl)octane-1-sulfonyl]-propionic acid (2.5 g, 6.5 mmol) and following the procedure as outlined in example 1, 641 mg of 2-[8-(1-Carboxy-ethanesulfonyl)octane-1-sulfonyl]-propionic acid hydroxyamidewas isolated as amber coloured oil.; Yield: 23%; MS: 434.0 (M+NH4)⁺; ¹H NoM (300 MHz, DMSO-dd: 8 1.27-3.23 (m, 22H), 3.33 (m, 2H), 8.9 (s, lH), 9.28 (s, 1H).

EXAMPLE 50 2-(4-Bromo-benzenesulfonyl)2-methyl-3-[(2-piperidine-1-yl-ethoxy)-phenyl]-propionic acid hydroxamide

[0325] 2-(4-Bromo-benzenesulfonyl)2-methyl-3-[4-(2-piperidine- 1 -yl-ethoxy)phenyl]-propionic acid ethyl ester was prepared according to general method as outlined in example 9. Starting from ethyl a-(4-bromophenyl-sulfonyl) acetate (5.0g, 16 mmol) and 1-[2-(4 chloromethylphenoxy)ethyl]-piperidine (4.97g, 16 mmol). Yield 6.1g (71%); tan oil; MS 541.1 (M+H)⁺.

[0326] 2-(4-Bromo-benzenesulfonyl)2-methyl-3-[(2-piperidine- 1 -yl-ethoxy)phenyl]-propionic acid was prepared according to general method as outlined in example 9. Starting from2-(4 bromo-benzenesulfonyl)2-methyl-3-[(2-piperidine-1-ylethoxy)phenyl]-propionic acid ethyl ester (6.5g, 20 mmol), ethanol (30 mL) and 10 N sodium hydroxide (15 ′xL). Yield 6.3g (100%); yellow solid mp 125-127 ° C.; MS 512.5 (M+H)⁺.

[0327] Starting from 2-4Bromo-benzenesulfonyl)2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)phenyl]-propiollic acid (6.1 g, 612 mmol) and following the procedure as outlined in example 1, 1.07 g of 2-(4Bromo-benzenesulfonyl)2-methyl-3-[(2-piperidine-1-yl-ethoxy)phenyl]-propionic acid hydroxyamide was isolated as light yellow solid; Yield: 17%; MS: 525.4 (M+H)⁺.

EXAMPLE 51 3-(4-Bromophenyl)N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-propionamide

[0328] Following the procedure as outlined in Example 9, 3-(4-bromo-phenyl)2-(4-methoxy-benzensulfonyl)2-methyl-propionic acid ethyl ester was prepared, starting from (3.0 g, 11 nmmol) 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and 4bromobenzyl bromide (3.0 g, 12 imol). Yield 4.67 g, 96%; Colorless oil; MS: 441 (M+H)⁺. 3-(4Bromo-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid was prepared starting from 3-(4bromo-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid ethyl ester (4.0 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 MnI). The resulting reaction mixture was worked up as outlined in Example 9. Yield 3.0 g, 78%. Low melting solid. MS: 413 (M+H)⁺.

[0329] Starting from 3-(4bromophenyl)2-(4-methoxy-benzenesulfgnyl)2-methyl-propionic acid (2.7 g, 6.5 =mol) and following the procedure as outlined in example 1, 2.26 g of 3-(4 bromophenyl)N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-propionamide was isolated as light colorless solid; Yield: 81%; mp 86-88 ° C.; MS: 429.8 (M+H)⁺; ¹H NM (300 MHz, CDCl₃): 5 1.42 (s,3H), 1.77 (bs, 1H), 3.26 (d, J=7.0 Hz, 1H), 3.68 (d, J=7.0 Hz, 1H), 3.85 (s, 3H), 7.01 -7.76 (m,8H), 9.71 - 9.88 (bs, 1H).

EXAMPLE 52 N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-naphthalen-2-yl-propionamide

[0330] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester was prepared, starting from (5.4 g, 20 mmol) 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and 2-bromomethyl naphthalene (4.4 g, 20 mmol). Yield 8.0 g, 97%; Colorless crystals, mp 182-184 ° C.; MS: 413 (M+H)⁺.

[0331] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester (4.6 g, 11 mmol) 4.2g (98%) of ²-(4-methoxy-benzenesulfonyl)2-methyl-3-naphthalen-2-yl-propionic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. mp144-146 ° C.; MS: 384.9 (M+H)⁺.

[0332] Starting from 2(4-methoxy-benzenesulfonyl)2-methyl-3-naphthalen-2-yl-propionic acid (2.4 g, 6.2 mmol) and following the procedure as outlined in Example 1, 1.6 g of N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-naphthalen-2-yl-propionamnide was isolated as a light colorless solid; Yield: 64%; mp 185 -187 ° C.; MS: 400.2 (M+I)⁺; ¹H NMR (300MHz CDC₁ ₃): 8 1.56 (s,3H), 3.28 (d, J=8.0 Hz, 1H), 3.81 (d, J=8Hz,1H), 3.93 (s,3H), 4.88 (bs, 1H), 7.02 - 7.92 (m, lIlH).

EXAMPLE 53 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)3-methyl-butyra ide

[0333] 2-(4-Methoxy-phenylsulfanyl)3-methyl-butyric acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of 2-(4-methoxy-phenylsulfanyl)3-methyl-butyric acid ethyl ester was isolated. Yield 99%; Light yellow oil; MS: 269 (M+H)⁺.

[0334] Starting from 2-(4-methoxy-phenylsulfanyl)3-methyl-butyric acid ethyl ester. (2.68 g 10 mmol) and following the procedure as outlined in Example 9 for oxidation, 3 g of 2-(4 methoxy-benzenesulfonyl)3-methyl-butyric acid ethyl ester was isolated as a colorless solid. yield: 99%; mp 53 ° C.; MS: 273 p+H)⁺.

[0335] Starting from 2-(4-methoxy-benzenesulfonyl)3-methyl-butyric acid ethyl ester (3 g, 10 mmol) 2.7 g (96%) of 2-(4-methoxy-benzenesulfonyl)3-methyl-butyric acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp 96 ° C.; MS: 273 (M+H)⁺.

[0336] Starting from 2-(4-methoxy-benzenesulfonyl)3-methyl-butyric acid (2.0 g, 7.34 mmol) and following the procedure as outlined in Example 9, 590 mg of N-hydroxy-2-(4-methoxy-benzenesulfonyl)3-methyl-butyramide was isolated as a colorless solid. Mp 220 ° C.; Yield 28%; MS: 288 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): o 0.88 (d, J=6.7 Hz, 3H), 1.07 5 (d, J=6.7 Hz, 3H), 2.09-2.20 (bs, 1H), 3.53 (d, J=9, 1H), 7.12-7.17 (m, 2H), 7.747.79 (m, 2H).

EXAMPLE 54 1-(4-Methoxy-benzenesulfonyl)cyclopentanecarboxylic acid hydroxyamide

[0337] Following the procedure as outlined in Example 9, 1-(4-methoxy-benzenesulfonyl) cyclopentanecarboxylic acid ethyl ester was prepared, starting from (3.0 g, 11.6 mmol) of 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and 1,4dibromobutane (2.4 g, 7.6 mnol). Yield 2.4 g, 78%; Colorless solid, mp 86-88 ° C.; MS: 313 (M+H)⁺. 1-(4-Methoxy-benzenesulfonyl)cyclopentanecarboxylic acid was prepared starting from I-(4-methoxy-benzenesulfonyl)cyclopentanecarboxylic acid ethyl ester (2.2 g, 7.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.66 g, 83%. Colorless solid; mp 112-115 ° C.; MS: 285 (M+H)⁺.

[0338] Starting from 1-(4-methoxy-benzenesulfonyl)cyclopentanecarboxylic acid (442 mg, 1.5 mmol) and following the procedure as outlined in Example 1, 410 mg of 1-(4 methoxy-benzenesulfonyl)cyclopentanecarboxylic acid hydioxyande was isolated as a colorless solid. mp 89-91 ° C.; Yield 88%; MS: 300 (M+H)⁺;¹H NMR (300 M1, CDC₁ ₃): o 1.65-1.82 (m, 4H), 2.17-2.42 (m, 4H), 3.87 (s, 3H), 7.0 (d, J=8Hz, 2H), 7.7 (bs, 1H), 7.72 (d, J=8 Hz, 2H), 9.73 (bs, 1H).

EXAMPLE 55 3-(2-Bromo-phenyl)N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-propionamide

[0339] Following the procedure as outlined in Example 9, 3-(2-bromo-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid ethyl ester was prepared, starting from (2.0 g, 7.3 nmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and 2-(bromo)benzyl bromide (2.0 g, 8 nmuol). Yield 3.1 g, 87%; Colorless oil; MS: 441 M+H)⁺. 3-(2-Bromo-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid was prepared starting from 3-(2-bromo-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid ethyl ester (3.0 g, 68 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.7 g, 63%. Waxy solid; MS: 414 (M+H)⁺.

[0340] Starting from 3-(2-bromo-phenyl)2-(4-methoxy-benzenesulfonyl)2-methyl-propionic acid (470 mg, 1.1 mmol) and following the procedure as outlined in Example 9, 380 mg of 3-2-bromophenyl)N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-propionamide was isolated as a colorless solid. mp 93-96 ° C.; Yield 77%; MS: 429 (M+H)⁺; ¹H No (300 MHz, CDC₁ ₃): 5 1.3 (s, 3H), 3.32 (d, J=7.0 Hz, lH), 3.69 (d, J=7.0 Hz, 1H), 3.82 (s, 3H), 6.92-7.89 (m, 8H).

EXAMPLE 56 2-(4-methoxy-benzenesulfonyl)2-methyl-5-phenyl-pent4enoic acid hydroxyamide

[0341] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent4enoic acid ethyl ester was prepared, startipg from (3.0 g, 11 mmol) 2-(4 methoxy-benzenesulfonyl)propionic acid ethyl ester and cinnamyl bromide (2.1 g, 11 mmol). Yield 3.51 g, 82%; Colorless oil; MS: 389 (M+H)⁺.

[0342] 2-(4-Methoxy-benzenesulfonyl)2-methyl-5-phenyl-pentfenoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-5-phenyl-penthenoic acid ethyl ester (3.0 g, 11 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.9 g, 68%; yellowish oil; MS: 361 (M+H)⁺.

[0343] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-5-phenyl-pent4-enoic acid (440 mg, 1.2 mmol) and following the procedure as outlined in Example 1, 420 mg of 2-(4-methoxy-benzenesulfonyl)2-methyl-5-phenyl-pent4enoic acid hydroxyamide was isolated as a colorless solid. mp 162-164 ° C.; Yield 92%; MS: 376 (M+H)⁺; ¹H NMR (300JMHz, CDC₁₃): 3 1.41 (s, 3H), 3.0-3.16 (m, 11), 3.30 (d, J=11 Hz, 2H), 3.92 (s, 3H), 5.9 - 6.1 (m, 11), 6.53 (d, J=l1Hz, 1H), 7.1-7.72 (m, 9H), 9.12 (bs,lH).

EXAMPLE 57 2-(4-methoxy-benzenesulfonyl)5-phenyl-2-(3-phenyl-propyl)pentanoic acid hydroxyamide

[0344] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)—S—phenyl-2-(3-phenyl-propyl)pentanoic acid ethyl ester was prepared, starting from (4.0 g, 15.8 mmol) 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and 3-bromopropyl benzene (6.4 g, 32 mmol). Yield 3.7 g, 47%; Colorless oil; MS: 495 (M+H)⁺.

[0345] 2-(4-Methoxy-benzenesulfonyl)5-phenyl-2-(3-phenyl-propyl)pentanoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)5-phenyl-2-(3-phenyl-propyl)pentanoic acid ethyl ester (2.0 g, 4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.18 g, 63%.Waxy solid; MS: 449.2 (M+H-H2O)⁺.

[0346] Starting from 2-(4-methoxy-benzenesulfonyl)5-phenyl-2-(3-phenyl-propyl)pentanoic acid (600 mg, 1.2 mmol) and following the procedure as outlined in Example 1, 420 mg of 2-(4-methoxy-benzenesulfonyl)5-phenyl-2-(3-phenyl-propyl)pentanoic acid hydroxyamide was isolated as a colorless solid. Mp 118-120 ° C.; yield 68%; MS: 482 (M'I+H)⁺; ¹H NhIR (300 MHz, CDC₁ ₃): 5 1.52 - 1.68 (m, 2H), 1.74 - 1.92 (m, 211), 1.98-2.20 (m, 4H), 2.58 - 2.72 (m,4H), 3.86 (s, 3H), 6.93 (d, J=11 Hz, 2H), 7.02-7.63 (m, 1OH), 7.81 (d, J=lI Hz, 2H).

EXAMPLE 58 2-allyl-2-(4-methoxy-benzenesulfonyl)pent4-enoic acid hydroxyamide

[0347] Following the procedure as outlined in Example 9, 2-allyl-2-(4-methoxy-benzenesulfonyl) pent4enoic acid ethyl ester was prepared, starting from (3.0 g, 11.6 mmol) 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and allyl bromide (4 ml, excess). Yield 3.6 g, 92%; Yellow oil; MS: 338 (M+l)⁺.

[0348] 2-Allyl-2-(4-methoxy-benzenesulfonyl)pent rnoic acid was prepared starting from 2-allyl-2-(4-methoxy-benzenesulfonyl)pentenoic acid ethyl ester (2.2 g, 6.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.76 g, 87%; yellowish oil; MS: 311 (M+H)⁺.

[0349] Starting from 2-allyl-2-(4-methoxy-benzenesulfonyl)pent4enoic acid (1.5 g, 4.8 nmnol) and following the procedure as outlined in Example 1, 1.5 g of 2-allyi-2-(4-methoxy-benzenesulfonyl)pentfenoic acid hydroxyamide was isolated as colorless solid Mp 1 14-116 OC; Yield 99%; MS: 326 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 8 1.62 (s, 1H), 2.70 - 2.80 (m,4H), 3.9 (s, 3H), 5.16 -5.27 (m, 4H), 5.81-5.94 (m, 2H), 7.12 (d,J=8 Hz,2H).

EXAMPLE 59 2-(4-methoxy-benzenesulfonyl)2-propyl-pentanoic acid hydroxyamide

[0350] 2-ailyl-2-(4-methoxy-benzenesulfonyl)pent4enoic acid hydroxyamide (326 mg, 1.0 mmol) (example 26) was dissolved in methanol (50 ml) and hydrogenated over 10% Pd/C (100 mg) at room temperature, under 49 psi pressure for 4 hours. At the end, the reaction mixture was filtered and methanol was removed. The resulting solid was crystallized from methanol. Yield: 250 mg, 75%; MS: 330 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): 8 0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9Hz, 2H), 7.76 (d,J=9 Hz, 2H).

EXAMPLE 60 2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)3-phenyl-propionamide

[0351] Following the procedure as outlined in Example 9, 2-benzyl-2-(4-methoxy-benzenesulfonyl) 3-phenyl-propionic acid ethyl ester was prepared, starting from (1.0 g, 3.8 mmol) of 2-(4 methoxy-benzenesulfonyl)acetic acid ethyl ester and benzylbromide (4 ml, excess). Yield 1.2 g, 72%; Yellow oil; MS: 439 (M+H)⁺.

[0352] 2-Benzyl-2-(4-methoxy-benzenesulfonyl)3-phenyl-propionic acid was prepared starting from 2-benzyl-2-(4-methoxy-benzenesulfonyl)3-phenyl-propionic acid ethyl ester (1.0 g, 2.2 mnmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield: 580 mg, 62%; Waxy solid; MS: 409 (iM-H).

[0353] Starting from 2-benzyl-2-(4-methoxy-benzenesulfonyl)3-phenyl-propionic acid (410 mg, 1 =mol) and following the procedure as outlined in Example 1, 225 mg of 2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)3-phenyl-propionamide was isolated as a waxy solid. Yield 52%; MS: 426 (M+H)⁺; ¹H NMR (300 MD, CDC₁₃): 5 3.25 (d, J=14 Hz, 2H), 3.52 (d, J=14 Hz, 2H), 3.9 (s, 3H), 6.93 (d, J=8Hz, 2H), 7.02 - 7.26 (m, 9H), 7.61 (d, J=8Hz, 2H), 7.87 (d, J=4Hz, 1H), 9.58 (bs, 1H).

EXAMPLE 61 N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-pyridin-3-yl-propionamide

[0354] To a stirred solution of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester (2.7 gm, 10 mmol), 3-picolyl chloride hydrochloride (3.2 g, 20 mmol). and triethyl benzylammonium chloride (1 g) in methylene chloride (400 ml), 10 N NaOH ( 30 ml) was added. The reaction was continued at room temp for 48 hours. At the end, the organic layer was separated and washed well with water. The organic layer was dried, filtered and concentrated. The crude product obtained was purified by silica-gel column chromatography. The column was eluted with 50% ethyl acetate: hexane. 2-(4-Methoxy-benzensulfonyl)2-methyl-3-pyridin-3-yl-propionic acid ethyl ester was isolated as brown oil. Yield 3.0 g, 82%; Brown oil; MS: 364 (M+H)⁺.

[0355] Starting from 2-(4-methoxy-benzenesulfonyl-2-methyl-3-pyndin-3-yl-propionic acid ethyl ester (2.5 g, 6.8 nmnol) 1.8 g (79%) of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-pyridin-3-yl-propionic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. mp 58 aC; MS: 336 (M+H)⁺.

[0356] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-pyridin-3-yl-propionic acid (410 mg, 1 mmol) and following the procedure as outlined in Example 1, 225 mg of N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3-pyridin-3-yl-propionamide was isolated as a colorless solid. Yield 52%; mp 98 ° C.; MS: 351 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.4 (s, 3H), 3.1 (d, J=9.0, -1H), 3.65 (d, J=9.1, 1H), 3.9 (s, 3H), 7-8.5 (m, 8H).

EXAMPLE 62 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyldecanoic acid hydroxyamide

[0357] Starting from 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester (7.5 g, 29 mmol) and 1-bromooctane (6.7 g, 35 nmol) 8 g of the mono octylated compound 2-(4-methoxy-benzenesulfonyl)ecanoic acid ethyl ester was isolated by following the procedure outlined in Example 9. Yield: 8.0 g 74%; MS: 370 (M+H)⁺.

[0358] Following the procedure as outlined in example 29, 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid ethyl ester was prepared, starting from (8.0 g, 21.6 mmol) of 2-(4-methoxy-benzenesulfonyl)decanoic acid ethyl ester and 3-picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 6.5 g, 68%; Brown oil; MS: 462 (M+H)⁺.

[0359] Starting from 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyldecanoic acid ethyl ester (5.0 g, 11 mmnol), 4.5g (91%) of 2-(4rmethoxy-benzenesulfonyl)2-pyridin-3-yl-methyl-decanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mvp 159 ° C.; MS: 434 (M+H)⁺.

[0360] Starting from 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-decanoic acid (2.5 g, 5.7 mmol) and following the procedure as outlined in Example 1, 1.4 g of 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyldecanoic acid hydroxyamide was isolated as colorless solid. Yield: 50%; mp 62 ° C.; MS: 448 (Ml+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 5 0.86 (t, 6.9 Hz, 3H), 1.25-2.17 (m, 14 H), 3.3 (d, J=14 Hz, 1H), 3.5 (d J=14 Hz, 1H), 3.9 (s, 3H), 6.8- 8.6 (m, 8H).

EXAMPLE 63 2-(4-Methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamnide

[0361] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5-methyl-hexenoic acid ethyl ester was prepared, starting from (6.0 g, 23 mmol) 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and isoprenyl bromide (3.0 g, 20 mmol). Yield 6.52 g, 86%; Colorless oil; MS: 327 (M+H)⁺.

[0362] Following the procedure as outlined in Example 29, 2-(4-methoxy-benzenesulfonyl)5-mehyl 2-pyridin-3-yimethyl-hexenoic acid ethyl ester was prepared, startng from (4.0 g, 12.2 mmol) of 2-(4-methoxy-benzenesulfonyl)5-methyl-hex-4-enoic acid ethyl ester and 3-picolylchloride hydrochloride (2.-1 g, 13 mmol). Yield 4.14 g, 81%; Brown oil; MS: 418 (MaH)⁺M

[0363] 2-(4-Methoxy-benzenes lony )—S—methyl-2-pyridin-3-ylmethyl-hex noic acid was prepared sting from 2-4-methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 3.2 g, 87%; ivory solid; mp 117-119 ° C.; MS: 390 (M+H)⁺.

[0364] Starting from 2-(4-methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hex4inoic acid (2.1 g, 5.4 mmol) and following the procedure as outlined in Example 1, 1.82 g of 2-(4 methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamide was iS isolated as a colorless solid. Yield: 82%; mp 89 - 92 ° C.; MS: 405 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 5 1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.78 (m, 2H), 3.3 (d, J=4.0 Hz, 1H), 3.63 (d, J=4.0 Hz, 1H), 3.82 (s, 3H), 5.26 (m, 1H), 7.12-7.88 (m, 6H), 8.27-8.33 (m, 2H).

EXAMPLE 64 2-Benzylwdiisopropylamino-N-hydroxy-2-(4-metho y-benzenesulfonyl)butyramide

[0365] Following the procedure as outlined in Example 29, 2-benzyl4-diisopropylamino-2-(4 methoxy-benzenesulfonyl)butyric acid ethyl ester was prepared, starting from (3.0 g, 8.5 nrol) of 2-(4-methoxy-benzenesulfonyl)3-phenyl-propionic acid ethyl ester (Example 9) and 2-diisopropylaminoethyl chloride hydrochloride (4.0 g, 20 mmol). Yield 3.2 g, 79%; Ivory solid, mp 89-91 ° C.; MS: 476.4 (M+H)⁺.

[0366] Starting from 2-benzyl4dEsopropylamino-2-(4-methoxy-benzenesulfonyl)butyric acid ethyl ester (3.53 gm, 7.5 mmol) 2.8 g (86%) of 2-benzyl4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)butyric acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 13&138 ° C.; MS: 448.5 (M+H)⁺.

[0367] Starting from 2-benzyl4diisopropylamino-2-(4-methoxy-benzenesulfonyl)butnmc acid (1.85 g, 4.1 mmol) and following the procedure as outlined in Example 1, 1.3 g of 2-benzy~l diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)butyramide was isolated as a low melting waxy solid; Yield: 68%; MS: 463.3 (M+H)⁺; 1H NMR (300 MD, CDC₁₃): δ 0.98 (d, J=11 Hz, 6H), 1.16 (d, J=11 Hz, 6H), 1.92 (m, 2H), 2.46 (m, 2H), 2.71 (m, 2H), 3.18 (m, 1H), 3.48 (m, 1H), 3.86 (s, 3H), 6.98 (d, J=8 Hz, 2H), 7.18 -7.22 (m, 5H, 7.92 (d, J=8 Hz, 2H), 8.12 (s, 1H).

EXAMPLE 65 3-Cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-propionamide

[0368] Following the procedure as outlined in Example 9, 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester was prepared, starting from (4.0 g, 15 mmol) 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and 1-bromomethyl cyclohexane (2.7 g, 15 mmol). Yield 5.0 g, 94%; Colorless oil; MS: 355 (M+H)⁺.

[0369] Following the procedure as outlined in Example 29, 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-propionic acid ethyl ester was prepared, starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester(1.5 g, 4.2 imol) and 3-picolyl chloride (1.0 g, 6 mmol). Yield 1.0 g, 38%; Colorless oil; MS 446 (M+H)⁺.

[0370] Starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-propionic acid ethyl ester (1.3 g, 2.9 mmol) l.Og (83%) of 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-propionic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 92 OC; MiS: 417.5 (M+H)⁺

[0371] Starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-propionic acid (1.0 g, 2.4 mmol) and following the procedure as outlined in Example 1, 80 mg of 3-cyclohexyl-N-hydroxy-2 -(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-propionamide was isolated as a colorless hydrochloride salt; Yield: 71%; mp 57-60 ° C.; MS: 433 (M+H)⁺; 1H NMR (300 MHz, CDC₁ ₃): 5 0.8-2.08 (mn, 13 H), 3.3 (d, J=14 Hz, 1H), 3.7 (d, J=14 Hz, 1H), 3.9 (s, 3H),'7.0 - 8.5 (m, 8H).

EXAMPLE 66 2-(4-Methoxy-benzenesulfonyl)4methyl-2-pyridin-3-ylmethyl-pentanoic acid hydroxyamide

[0372] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)4methyl pentanoic acid ethyl ester was prepared, starting from (5.0 g, 20 mmol) 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and 1-bromo-2-methyl propane (2.6 g, 20 mmol). Yield 6.0 g, 95%; Colorless oil; MS: 315 (M+H)⁺.

[0373] Following the procedure as outlined in Example 29, 2-(4-methoxy-benzenesulfonyl)4 methyl-2-pyridin-3-ylmethyl-penanoic acid ethyl ester was prepared, staring from (3.1 g, 10 mmol) of 2-[(4-methoxy-benzenesulfonyl)Amethyl pentanoic acid ethyl ester and 3-picolyl chloride hydrochloride (1.8 g, 11 mmol). Yield 3.0 g, 75%; Colorless oil; MS: 406 (M+H)⁺.

[0374] Starting from 2-(4-methoxy-benzenesulfonyl)4methyl-2-pyridin-3-ylmethyl-pentanoic acid ethyl ester (1.2 g, 2.9 mmol) l.Og (91%) of 2-(4-methoxy-benzenesulfonyl)4-methyl-2-pyridin-3-ylmethyl-pentanoic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 188-186 ° C.; MS: 378 (M+H)⁺.

[0375] Starting from 2-(4-methoxy-benzenesulfonyl)Dmethyl-2-pyridin-3-ylmethyl-pentanoic acid (800 mg, 2.1 mmol) and following the procedure as outined in Example 1, 180 mg of 2-(4-methoxy-benzenesulfonyl)4methyl-2-pyridin-3-ylmethyl-pentanoic acid hydroxyamide was isolated as a colorless solid; Yield: 21%; mp 78 ° C.; MS: 393.4 (M+H)⁺; ¹H NMR (300 Mz, CDCl₃): o 0.65 (d, 6.3 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 3H), 6.8 -8.5 (m, 10H).

EXAMPLE 67 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)2-methyl-3uinolin-6-yl-propionamide

[0376] Following the procedure as outlined in Example 29, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3quinolin-6-yl-propionic acid ethyl ester was prepared, starting from (5.2 g, 20 nmmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and 7-bromomethyl quinoline (4.4 g, 20 mmol). Yield 4.5 g, 54%; Pale yellow solid; mp 86 ° C.; MS: 414 (M+H)⁺.

[0377] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-quinolin-6yl-propionic acid ethyl ester ( 3.0 gm, 7.2 mmol) 2.5g (90%) of 2-(4-methoxy-benzenesulfonyl)2-medtyl-3uinoli 6yl-propionic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. mp 106-108 IC; MS: 386.4 (M+II)⁺.

[0378] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-quinolin-&yl-propionic acid (2.0 gm, 5.2 mmol) and following the procedure as outlined in Example 1, 1.2 g of N-hydroxy-2-(methoxy-benzenesulfonyl)2-methyl-3Swnolin-6-yl-propionide was isolated as a colorless solid; Yield: 57%; mp 206 IC; MS: 401.4 (M+H)⁺; ¹H NMR (300 MD, CDC₁ ₃): 8 1.4 (s, 3H), 3.19 (m, 1H), 3.8 4.0 (m, 4H), 7.1 -8.95 (m, 12H).

EXAMPLE 68 2-(4-Methoxy-benzenesulfonyl)6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide

[0379] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-4-phenoxy-hexanoic acid ethyl ester was prepared, starting from (2.5 g, 10 mmol) 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and 1-bromo4-phenoxy butane (2.2, 10 mmol). Yield 3.8 g, 93%; Colorless oil; MS: 407 (M+H)⁺.

[0380] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester was prepared, starting from (3.1 g, 10 mmol) 2-(4-methoxy-benzenesulfonyl)6-phenoxy-hexanoic acid ethyl ester and 3-picolyl chloride (1.8 g, 11 mnmol). Yield 3.5 g, 71%; Colorless oil; MS: 498 (M+H)⁺.

[0381] Starting from 2-(4-methoxy-benzenesulfonyl)6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester (3.0 g, 6.0 nmmol), 2.8g (Yield: Quantitative) of 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 148-151 IC; MS: 470.5 (M+H)⁺.

[0382] Starting from 2-(4-methoxy-benzenesulfonyl)6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid (2.0 g, 4.3 mmol) and following the procedure as outlined in Example 1, 1.5 g of 2-(4-methoxy-benzenesulfonyl)6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was isolated as a colorless solid; Yield: 72%; mp 68 IC; MS: 485.5 (M+H)⁺; ¹H NMR (300 MHz, CDC₁ ₃): 5 1.5 - 2.5 (m, 8H), 3.4 (bs, 2H), 3.8 (s, 3H), 6.8 - 8.7 (m, 13H).

EXAMPLE 69 2-(4-Methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide

[0383] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)5-hexanoic acid ethyl ester was prepared, starting from (10.0 g, 39 mmol) 2-(4-methoxy-benzenesulfonyl)acetic acid ethyl ester and 1-bromo-3-methyl butane ( 6.0 g, 40 mnmol). Yield 8.5 g, 62%; Colorless oil; MS: 329 (M+H)⁺.

[0384] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester was prepared, starting from (6.0 g, 18 mmol) of 2(4-methoxy-benzenesulfonyl)5-methyl-hexanoic acid ethyl ester and picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 4.5 g, 60%; Brown oil; MS: 420 (M+H)⁺.

[0385] Starting from 2-(4-methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester (3.0 g, 7.1 mnmol) 2.6g (92%) of 2-(4-methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hexanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp: 173 C; MS: 392 (iM+H)⁺.

[0386] Starting from 2-(4-methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hexanoic acid (1.0 g, 2.5 mmol) and following the procedure as outlined irrExample 1, 800 mg of 2-(4 methoxy-benzenesulfonyl)5-methyl-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was isolated as a colorless solid; The hydrochloride was prepared by passing hydrogen chloride gas through methanol solution of the hydroxyamide. Yield: 72%; mp 62 ° C. (HCI salt); MS: 408 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): 5 0.76 (m, 6H), 1.2 -2.0 (m, 5H), 3.5 (bq, 2H), 7.1 - 8.8 (m, 8H), 11.1 (bs,lH).

EXAMPLE 70 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide

[0387] (4-Methoxy-phenylsulfanyl) -acetic acid tert-butyl ester was prepared according to the general method as outlined in Example 1. Starting from the corresponding 1-bromo tert-butyl acetate (5.3 g, 27 minol) and 4-methoxybenzenethiol (3.7 g, 27 mmol), 6.4 g of the product was isolated. Yield 98%; Light yellow oil; MS: 255 (M+H)⁺.

[0388] 2-(4-Methoxy-benzenesulfonyl)acetic acid tert-butyl ester was prepared according to the general method as outlined in Example 9. Starting from 2-(4-methoxy-benzenesulfanyl)acetic acid tert-butyl ester (5.0 g, 20 mmol) and 3-chloroperoxybenzoic acid 57% (12.0g, 40 mmol), 5.3 g of the product was isolated. Yield 92%; Waxy solid; MS: 287.1 (M+)⁺.

[0389] 2-(4-Methoxy-benzenesulfonyl)pyridin-3-ylpropionic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-methoxy-benzenesulfonyl)acetic acid tert-butyl ester (20.0 g, 70.0 mmol) and 3-picolyl chloride (728 g, 44.4 mmol), 10.5 g of the product was isolated by silica gel chromatography (50% ethyl acetate: hexane). Yield 63%; white solid; mp 93-94 ° C.; MS: 378.0 (M+H)⁺.

[0390] 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-hexanoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-methoxy-benzenesulfonyl)pyridin-3-ylpropionic acid tert-butyl ester (2.0 g, 5.3 mrnol) and n-butyl bromide (0.73 g, 5.3 mmol), 1.20 g of the product isolated. Yield 52%; yellowish gum; MS: 434.3 (M+H)⁺.

[0391] A mixture of the 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-hexanoic acid tert-butyl ester (1.1 g, 2.5 mmol), in methylene chloride/ TFA (1:I)was stirred at room temperature for about 2 hours. The solvents were then evaporated and the 2-}4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid was purified by silica gel chromatography (30% methanol/methylene chloride). Yield 0.90 g, 94%; white solid$'mp 10 ° C.; NMS: 376.1 (M−H).

[0392] 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-yhmethyl-hexanoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-hexanoic acid (0.31 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 g of the product isolated. Yield 37%; pale yellowish solid; mp 65 ° C.; MS: 392.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6) 8 0.80 (t, 1 =7.2 Hz, 3H), 1.10-1.25 (m, 2H), 1.25-1.50 (m, 2H), 1.70-2.00 (m, 2H), 3.53 (d, J=14.4 Hz, 1H), 3.62 (d, J=14.4 Hz, 1H), 3.88 (s, 3H), 7.15 (d, J=8.9 Hz, 2H), 7.71 (d, J=8.9 Hz, 2H), 7.90-8.00 (m, 1H), 8.40-8.45 (m, 1H), 8.70-8.85 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm-¹): 3064m, 2958s, 2871m, 1671m.

EXAMPLE 71 2-(4-methoxy-benzenesulfonyl)2-oct-2-ynyl-dec-4-ynoic acid hydroxyamide.

[0393] The title compound was prepared according to the procedure as outlined in example 9. Starting from 2-(4-methoxy-benzenesulfonyl)acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-octyne (3.80 g, 20 mmol), 4.4 g of the product isolated. Yield 100%; yellowish gum; MS: 446.9 (M+H)⁺.

[0394] 2-(4-Methoxy-benzenesulfonyl)2-oct-2-ynyl-dec4-ynoic acid was prepared according to the method as outlined in example 70. Starting from 2-(4-methoxy-benzenesulfonyl)2-oct-2-ynyl-decynoic acid tert-butyl ester (4.40 g, 10.0 mmol), 2.0 g of the product isolated. Yield 49%; white solid; mp 61° C.; MS: 345.1 (M−H).

[0395] 2-(4-Methoxy-benzenesulfonyl)2-oct-2-ynyl-dec4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)2-oct-2-ynyl-dec4fynoic acid (0.36 g, 0.81 imnol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.25 ; of the product isolated. Yield 62%; white solid; mp 83-84 ° C.; 462.0 (Mvf+H)⁺; ¹H NMR (300 iMHz, DMSO-d₆) 5 0.82-0.90 (m, 6H), 1.15-1.45 (m, 12H), 1.90-2.05 (m, 4H), 2.86 (brd, J=17.0 Hz, 2H), 3.00 (brd, J=17.0 Hz, 2H), 3.87 (s, 3H), 7.15 (d, J=10.0 Hz, 1H), 7.71 (d, J=10.0 Hz, 1H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm-l): 3344s, 3208m, 2930m, 2870m, 1677s, 1592s; Anal. Calc'd for C₂₅H₃₅NO₅S: C, 65.05; H, 7.64; N, 3.03. Found: C, 65.26; H, 7.68; N, 2.90.

EXAMPLE 72 2-(4-Methoxy-benzenesulfonyl)2-but-2-ynyl-hextynoic acid hydroxyamide

[0396] 2-(4-Methoxy-benzenesulfonyl)2-but-2-ynyl-hex4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-methoxy-benzenesulfonyl)acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-butyne (2.68 g, 20 mmol), 3.50 g of the product was isolated. Yield 90%; white solid; mp 85-87 ° C.; MS: 391.0 (M+H)⁺.

[0397] 2-(4-Methoxy-benzenesulfonyl)2-but-2-ynyl-hexfynoic acid was prepared according to the procedure as outlined in example 70. Starting from 2-(4-methoxy-benzenesulfonyl)2-but-2-ynyl-hextynoic acid tert-butyl ester (3.0 g, 7.7 mmol), 2.5 g of the product isolated. Yield 97%; white solid; mp 141-143 ° C.; MS: 333.1 (M−H).

[0398] 2-(4-Methoxy-benzenesulfonyl)2-but-2-ynyl-hex~ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)2-but-2-ynyl-hex4ynoic acid (0.27 g, 0.81 mmol) and hydroxylnine hydrochloride (0.70 g, 10 mmol), 0.23 g of the product was isolated. Yield 89%; white solid; mp 135-137° C.; MS: 349.9 (M+H)⁺I; ¹H NMR (300 MHz, DMSO-d6) 8 1.67 (s, 6H), 2.70 3.10 (m, 4H), 3.88 (s, 3H), 7.15 (d, J=10.0 Hz, 2H), 7.71 (d, J=10.0 Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm-l): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.

EXAMPLE 73 2-(4-Methoxy-benzenesulfonyl)2-prop-2-ynyl-pent4ynoic acid hydroxyamide

[0399] 2-(4-Methoxy-benzenesulfonyl)2-prop-2-ynyl-pent4ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-methoxy-7-benzenesulfonyl)acetic acid tert-butyl ester (2.0 g, 7.0 mmol) and propargyl bromide (1.77 g, mol), 1.90 g of the product was isolated. Yield 75%; white solid; mp 113-115° C.; MS: 362.1 (M+H)⁺.

[0400] 2-(4-Methoxy-benzenesulfonyl)2-prop-2-ynyl-pent4-ynoic acid was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent4-ynoic acid tert-butyl ester (1.70 g, 4.7 mmol), 1.30′g of the product isolated. Yield 90%; white solid; mp 156° C.; MS: 305.1 (M−H).

[0401] 2-(4-Methoxy-benzenesulfonyl)2-prop-2-ynyl-pent4ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4-methoxy-benzenesulfonyl)2-prop-2-ynyl-pentlynoic acid (0.25 g, 0.81 nmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolated. Yield 85%; white solid; mp 156° C.; MS: 321.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6) 5 2.00-2.13 (m, 2H), 3.00 3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm-i): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s; Anal. Calc'd for C₁₅Hl₅NO₅S: C, 56.07; H, 4.70; N, 4.36.

[0402] Found: C, 55.65; H, 4.67; N, 4.10.

EXAMPLE 74 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-dec4ynoic acid hydroxyamide

[0403] The title compound was prepared according to the procedure as outlined in Example 38. Starting from 2-(4-methoxy-benzenesulfonyl)pyridin-3-ylpropionic acid tert-butyl ester (2.20 g, 5.8 inmol) and I-bromo-2-octyne (1.14 g, 6 mmol), 2.60 gm of the product isolated. Yield 92%; yellowish gum; MS: 486.0 (M+H)⁺.

[0404] A mixture of the 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-dec4ynoic acid tert-butyl ester (2.60 g, 5.35 mmol), in methylene chlorideJFFA (1: 1) is stirred at room temperature for about 2 hours. (Ref. example 70) The solvents are then evaporated and the 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-dec4ynoic acid was purified by silica gel chromatography (-30% methanol/methylene chloride). Yield: 2.0 , 87%; White solid; mp 146° C.; MS: 428.1 (M−H).

[0405] 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-dec4-ynoic acid hydroxyamide was prepared according to the procedure outlined in Example 1. 8taing from 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-decfynoic acid (0.71 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 g of the product was isolated. Yield 67%; off-white solid; mp 65° C.; MS: 445.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6) 5 0.84 (t, J=6.8 Hz, 3H), 1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, J 17.9 Hz, 1H), 2.90 (d, J=17.9 Hz, 1H), 3.50 (d, J=13.7 Hz, 1H), 3.74 (d, J=13.7 Hz, 1H), 3.89 (s, 3H), 7.19 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.85-7.89 (m, 1H), 8.37-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm-1): 3157m, 3095m, 2954s, 2932s, 2858m, 1671m, 1593s; Anal. Calc'd for C₂₃H₂₈N₂O₅S-HC1-0.9H₂O: C, 55.56; H, 6.24; N, 5.63. Found: C, 55.84; H, 6.19; N, 5.59.

EXAMPLE 75 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-pent4fynoic acid hydroxyamide

[0406] 5 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-pent4ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 38. Starting from 2-(4-methoxy-benzenesulfonyl)pyridin-3-ylpropionic acid tert-butyl ester (3.77 g, 10 immol) and propargyl bromide (1.74 g, 13 mmol), 2.50 g of the product was isolated. Yield 60%; yellowish solid; Mp 132-133° C.; MS: 416.0 (M+H)⁺.

[0407] 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-pent~ynoic acid was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-pent~ynoic acid tert-butyl ester (2.0 g, 4.8 mmol), 1.2 g of the product isolated. Yield 69%; white solid; mp 119-121° C.; MS: 358.1 (M−H).

[0408] 2-(4-Methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-pent4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)2-pyridin-3-ylmethyl-pent ⁴ynoic acid (0.29 g, 0.81 im=ol) and hydroxylamine hydrochloride (0.70 m, 10 mmol), 0.065 g of the product was isolated. Yield 25%; off-white solid; mp 70° C.; MS: 375.0 (I+H)⁺; ¹H NMR (300 MHz, DMSO-d6) 3 1.19 (brs, 1H), 2.90-3.00 (m, 2H), 3.55 (d,=13.8 Hz, 1H), 3.67 (d, J=13.8 Hz, 1H), 3.89 (s, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.80-7.89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm-1): 3168m, 3095s, 1670m, 1593s.

EXAMPLE 76 2-(4Fluoro-benzenesulfonyl)2-pyridin-3-ylmethyl-hex4-ynoic acid hydroxyamide

[0409] 2-(4Fluoro-benzenesulfanyl)acetic acid tert-butyl ester was prepared according to the procedure as outlined in Example 1. Starting from 4fluorothiophenol (30.0 g,230 mmol) and tert-butyl bromoacetate (45.67 g, 230 nmmol), 53.4 g of the product was isolated. Yield 100%; pale yellowish oil; MS: 243.1 (M+H)⁺.

[0410] 2-(4Fluoro-benzenesulfonyl)acetic acid tert-butyl ester was prepared according to the general method as outlined in Example 9. Starting from 2-(4-fluoro-benzenesulfanyl)acetic acid tert-butyl ester (48.4 g, 200 imol) and 3-chloroperoxybenzoic acid (121.3g (57%), 400 nmol), 48.0 g of the product was isolated. Yield 88%; pale yellowish oil; MS: 275.1 (M+H)⁺.

[0411] The title compound was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-fluoro-benzenesulfonyl)3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo-2-butyne (0.67 g, 5.0 mmol), 2.18 g of the product was isolatei Yield 100%; yellowish gum; MS: 419.2 (M+H)⁺.

[0412] 2-(4-Fluoro-benzenesulfonyl)2-pyridin-3-ylmethyl-hex~ynoic acid was prepared according to the method as outlined in Example 38. Starting from 2-(4-fluorobenzenesulfonyl)-2-pyridin-3-ylmethyl-hex4ynoic acid tert-butyl ester (2.1 g, 5.0 mmol), 1.20 g of the product was isolated. Yield 67%; off-white solid; mp 150° C.; MS: 360.2 (M−H).

[0413] 2-(4-Fluoro-benzenesulfonyl)2-pyridin-3-ylmethyl- hex4ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)2-pyridin-3-ylmethyl-hexyrynoic acid (0.29 g, 0.81 mnmol) and hydroxylamine hydrochloride ( 0.70 g, 10 mmol), 0.15 g of the product was isolated. Yield 45%; white solid; mp 190° C.; MS: 377.2 (M+H)⁺; ¹H NMIR (300 MHz, DMSO-d6) 5 1.60 (s, 3H), 2.70-3.00 (m, 2H), 3.53 (d, J=13.8 Hz, 1H), 3.74 (d, J=13.8 Hz, 1H), 7.50-7.58 (m, 2H), 7.80-7.95 (m, 3H), 8.35-8.40(m, 1H), 8.74-8.79 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm-1): 3154m, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s; Anal. Calc'd for C₁₈Hl₇FN₂O₄SlHCI- 0.5H₂0: C, 51.24; H, 4.54; N, 6.64. Found: C, 51.21; H, 4.35; N, 6.46.

EXMPLE 77 2-(4-Fluoro-benzenesulfonyl)2-pyridin-3-ylmethyl-dec4fynoic acid hydroxyamide

[0414] The title compound was prepared according to the procedure as outlined in Example 9. Starting, from 2-(4-fluoro-benzenesulfonyl)3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo-2-octyne (0.95 g, 5.0 mmol), 1.80 g of the product was isolated. Yield 56%; yellowish gum; MS: 474.3 (M+H)⁺.

[0415] 2-(4-Fluoro-benzenesulfonyl)2-pyridin-3-ylmethyl-decfynoic acid was prepared according to the method as outlined in Example 70. Starting from 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyldec4fynoic acid tert-butyl ester (1-80 g, 3.8 mmol), 1.40 g of the product was isolated Yield 88%; off-white solid; mp 123-124° C.; MS: 416.3 (M-.-.

[0416] 2-(4Fluorobenzenesulfonyl)2-pyridin-3-ylmethyldec~ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)2-pyridi-3-ylmethyldec~ynoic acid (0.67 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.22 g of the product was isolated Yield 29%; white solid; mp 180-182° C.; MS: 433.2 (M+H)⁺; ¹H NMR (300 MHz, DMSOd4) s 0.84 (t, I=6.8 Hz, 3H), 1.20-1.40 (m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, J=19.9 Hz, 1I), 2.94 (d, J=19.9 Hz, 1H), 3.54 (d, J=13.7 Hz, 1H), 3.75 (d, J=13.7 Hz, 1H), 7.4w 7.60(m, 2H), 7.70-8.00 (m, 3H), 8.30-8.40 (m, 1H), 8.70-8.80 (m, 2E), 11.1 (brs, 1H); IR (KBr, cm-1): 3154m, 3105s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631m. Anal. Calc'd for C₂2H₂5FN₂0₄S.HCl: C, 56.34; H, 5.59; N, 5.97. Found: C, 56.18; H, 5.54; N,5.76.

EXAMPLE 78 2-(4Fluoro-benzenesulfonyl)2-but-2-ynyl-hextynoic acid hydroxyamide

[0417] 2-(4Fluoro-benzenesulfonyl)2-but-2-ynyl-hextynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-fluoro-benzenesulfonyl)acetic acid tert-butyl ester (4.87 g, 20 mmol) and 1-bromo-2-butyne (5.36 g, 40 mmol), 6.0 g of the product was isolated. Yield 77%; white solid; mp 85° C.; MS: 379.1 (M+H)⁺.

[0418] 2-(4Fluoro-benzenesulfonyl)2-but-2-ynyl-hex~ynoic acid was prepared according to the procedure as outlined in Example 70, starting from 2-(4fluoro-benzenesulfonyl)2-but-2-ynyl-hex4-ynoic acid tert-butyl ester (3.50 g, 8.47 immol), 2.35 g of the product was isolated. Yield 79%; white solid; mp 129-131° C.; MS: 642.8 (2M-H).

[0419] 2-(4Fluoro-benzenesulfonyl)2-but-2-ynyl-hex4ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. . Starting from 2-(4-fluoro-benzenesulfonyl)2-but-2-ynyl-hex4ynoic acid (0.26 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.21 g of the product was isolated. Yield 77%; white solid; mp 161-163° C.; MS:338.1(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) o 1.67 (s, 61), 2.80-3.10 (m, 4H), 7.51 (dd, J=9.0, 9.0 Hz, 2H), 7.87 (m, 21), 9.26 (brs, 1H), 10.95 (brs, 1H); IR (KBr, cm-i): 3336s, 3245m, 1681s, 1589m, 1493m; Anal. Calc'd for C₁₆Hl₆FN0₄S: C, 56.96; H, 4.78; N, 4.15. Found: C, 56.59; H, 4.75; N, 4.04.

EXAMPLE 79 2-(4-Methoxy-benzenesulfonyl)5-methyl-2-(3-methyl-but-2-enyl)hexAenoic acid hydroxyamide

[0420] Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)hex~enoic acid ethyl ester was prepared, startinO from (5.0 g, 20 mmol) 2-(4-methoxy-benzenesulfonyl)acedc acid ethyl ester and isoprenyl bromide (6.0 g, 40 18 mmol). Yield 7.0 g, 88%; Colorless oil; MS: 395 (M+H)⁺.

[0421] Starting from 2-(4-methoxy-benzenesulfonyl)5-methyl-2-(3-methyl-but-2-enyl)hextenoic acid ethyl ester (3.5 g, 9 mmol), 3.3g (97%) of 2-(4-methoxy-benzenesulfonyl)5-methyl-2-(3-methyl-but-2-enyl)hex~enoic acid was isolated as a colorless oil by following the procedure as outlined in Example 9. MS: 365 (M−H).

[0422] Starting from 2-(4-methoxy-benzenesulfonyl)5-methyl-2-(3-methyl-but-2-enyl)hexpenoic acid (2.6 g, 7.0 mmol) and following the procedure as outlined in Example 1, 1.36 g of 2-(4-methoxy-benzenesulfonyl)5-methyl-2-(3-methyl-but-2-enyl)hexAenoic acid hydroxyamide was isolated as a colorless solid. Yield: 67%; mp 93 - 96 ° C.; MS: 383 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): o 1.68 (s, 6H), 1.73 (s, 6H), 2.72 (m, 4H), 3.82 (s, 3H), 5.12 (m, 211), 6.92 (d, J=8 Hz, 2H), 7.33 (bs, 1H), 7.72 (d, J=8 Hz, 2H), 9.71 (bs, 1H).

EXAMPLE 80 2-(4-methoxy-phenylsulfanyl)heptanoic acid hydroxyamide.

[0423] 2-(4-Methoxy-phenylsulfanyl)heptanoic acid ethyl ester (13.8 g, 98%) was prepared according to the general method as outlined in example 1 starting from ethyl 2-bromoheptanoate (1 -1 g, 47 mmol) and 4-methoxythiophenol (6g, 42.8 mmol), as a yellow oil; MS: 297.2 (M+H)⁺.

[0424] 2-(4-Methoxy-phenylsulfanyl)heptanoic acid was prepared starting with 2(4-methoxy-phenylsulfanyl)heptanoic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 1. Yield 3 g (83%). yellow oil. MS: 267.1 (M−H).

[0425] Starting from 2-(4-methoxy-phenylsulfanyl)heptanoic acid (2.49 g, 9.32 mmol) and following the procedure as outlined in example 1, 1.83 g of 24(methoxy-phenylsulfanyl)heptanoic acid hydroxyamide was isolated as an off white solid. Mp 90-95 ° C.; Yield 70%; MS: 284.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): 5 0.826 (t, J=6.9 Hz, 3H), 1.135-1.76 (m, 8H), 3.35 (m, 1H), 3.82 (s, 3H), 6.91-7.49 (m, 4H).

EXAMPLE 81 (49A) 2R*-(4-methoxy-phenyl- S*- sulfinyl)heptanoic acid hydroxyamide and (49B) 2S*-(4-methoxy-phenyl- R*- sulfinyl)heptanoic acid hydroxyamide

[0426] Starting from 2-(4-methoxy-phenylsulfanyl)heptanoic acid hydroxyamide (1.69 a, 6 mmol) and following the procedure outlined in example 5, the two diastereomers of 2-(4-methoxy-phenylsulfinyl)heptanoic acid hydroxyamide were separated on a silica gel column using 75% ethyl acetate:hexanes. The less polar isomer, 2R*-(4-methoxy-phenyl- S*- sulfmyl)heptanoic acid hydroxyamide was isolated as a white powder. Yield: 390 mg (22%); mp 115 ° C.; MS: 300.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): 0.828 (t, J=6.2 Hz, 3H), 1.18-1.23 (m, 6H), 1.73-1.99 (m, 2H), 3.11-3.15 (m, 1H), 3.82 (s, 3H),'7.′09-P.61 (m, 4H). The more polar isomer, 2S*-(4-methoxy-phenyl- R*- sulfinyl)heptanoic acid hydroxyamide was isolated as a gray solid. Yield: 200 mg (1 1%o); mp 112 ° C.; MS: 300.0 (M+H)⁺, ¹H NMR (300 MHz, DMSO-d₆): 3 0.754 (t, J=6.9 Hz, 3H), 1.014-1.121 (m, 6H), 1.58-1.89 (m, 2H), 3.10-3.15 (m, 1H), 3.834 (s, 3H), 7.13-7.65 (m, 4H).

EXAMPLE 82 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-morpholin4-yl-ethoxy)-phenyl]-propionic hydroxyamide hydrochloride.

[0427] Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)2-methyl 3-[4-(2-morpholin-1-yl-ethoxy)phenyl]-propionic acid ethyl ester was prepared, starting from (4.0g, 15 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester and 4-(morpholin-1-yl-ethoxy)benzyl chloride hydrochloride (2.9 g, 10 mmol). Yield 4.8 g, 98%; Brown oil; MS: 492 (M+H)⁺.

[0428] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-morpholin-1-yl-ethoxy) phenyl-propionic acid ethyl ester (4.0 gm, 8.1 mmol) 3.2 g (Yield: 84%) of 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 171 ° C.; MS: 464 (M+H)⁺.

[0429] Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-morpholin-1-yl-ethoxy) phenyl]-propionic acid (4.0 g, 8.6 imnol) and following the procedure as outlined in example 1, 2.5 gof 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-morpholin-1-yl-ethoxy) phenyl]-propionic hydroxyamide was isolated as colorless solid. The hydrochloride salt was prepared by reacting the free base with methanolic hydrogen chloride at 0 ° C. Yield: 2.5 g, 60%; mp 98° C.; MS: 479 (M+H)⁺; ¹H NMIR (300 MHz, CDCl₃): 1.36 (s, 3H), 3.8 - 12.6 (m, 16 H), 3.9 (s, 3H), 4.1 - 4.3 (m, 1H), 6.6 (d, J=8 Hz, 2H), 6.96 (d, J=9 Hz, 2H), 7.1 (d, 8 Hz, 2H), 7.84 (d, 9 Hz, 2H), 10.8 (bs, 1H).

EXAMPLE 83 1-Benzyl-4-(4-methoxy-benzenesulfonyl)piperidine~carboxylic Acid hydroxyamide

[0430] To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) and anhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), α-bromo ethyl acetate (3.3 gm, 20 mnnol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H₂O and 0.5 N NaOH solution. The organic layer was flier washed well with water, dried over MgSO₄, filtered and concentrated (4-methoxy-phenylsulfanyl)acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%); MS; 227 (M+H)⁺.

[0431] To a stirred solution of 60% 3chloroperoxybenzoic acid (14.0 gm, 40 mmol) in methylene chloride (100 m1l) at 0° C., (4-methoxy-phenylsulfanyl)acetic acid ethyl ester (4.4 g, 20 mmcl) in CH₂CQ₂ (15 ml) was added slowly. The reaction mixture turned cloudy and was stirred at room temperature for 6 hours. The reaction mixture was then diluted with hexanes (300 ml) and stirred for 15 minutes. The solids were filtered off and Na₂SO₃ solution was added to the organic layer which was stirred for at least 3 hours before the mixture was extracted with CHCl₃ and washed with H₂O.The organic layer was dried over MgSO₄, filtered and concentrated and the colorless (4-methoxy-phenylsulfonyl)acetic acid ethyl ester was isolated as an oil. Yield: 100%; MS: 259.1 (M+H)⁺.

[0432] To a stirred solution of diethanol amine (10.5 g, 100 mmol), and anhydrous K₂CO₃ (30 gm, excess) in dry acetone (250 ml), benzyl bromide (17.2 gm, 100 =mol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H₂O . The organic layer was further washed well with water, dried over MgSO₄, filtered and concentrated. Colorless oil. Yield: 19.0 g,97%; MS: 196 (M+H). N-Benzyldiethanolarrine (9.75 g, 50 mmol) was dissolved in saturated methanolic hydrochloric acid and concentrated to dryness. The hydrochloride thus formed was dissolved in methylene chloride (300 ml) and thionyl chloride (20 g, excess) was added dropwise and stirred at room temperature for 1 hr. At the end reaction mixture was concentrated to dryness and the product bis-(2-chloro-ethyl)benzyl amine hydrochloride was used for further transformation with out any purification. Yield: 13.0 g, 97%; Mp: MS: 232 (M+H).

[0433] To a stirred solution of bis-(2-chloro-ethyl)benzyl amine hydrochloride (6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K₂CO₃ (30 gm, excess) in dry acetone (250 ml), f4-methoxy-phenylsulfonyl)acetic acid ethyl ester (6.12 gm, 24 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 16 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H₂0 . The organic layer was further washed well with water, dried over MSO0₄, filtered and concentrated. The dark brown reaction mixture was purified by silica gel coumn chromatography by eluting it with 30% ethylacetate: hexane and the product 4-(4-Methoxy-benzenesulfonyl)1-benzyl-piperidine-4-carboxylic acid ethyl ester was isolated as Brown oil. Yield: 6.0 g, 60%; MS: 418 (M+H).

[0434] 4-(4-Methoxy-benzenesulfonyl)1-benzyl-piperidine-4-carboxylic acid ethyl ester (5.0 g, 11.9 mmol) was dissolved in MeOH/HF (1:1, 200 ml) and stirred at room temperature for 72 hrs. At the end reaction mixture was concentrated and the product was nuetralised with con. Hcl by dissolving it in water (200 ml). After the nuetralization reaction mixture was concentrated to dryness. Ice cold water (100 ml) was added to the solid and filtered. The product 4-(4 Methoxy-benzenesulfonyl)1-benzyl-piperidine-4-carboxylic acid was dried at 50 C and taken to next step with out any purification. Colorless solid. Yield: 3.2 g, 69% ; MS: 390 (M+H).

[0435] To a stirred solution of 4-(4-Methoxy-benzenesulfonyl)1-benzyl-piperidinencarboxylic acid (2.0 g, 5.1 mmol) and DMEF (2 drops) in CH₂C₁₂ (100 ml) at OC, oxalyl chloride (1.0 gn, 8 mmol) was added in a drop-wise manner. After the addition, the reaction miture was stirred at room temperature for 1 hour. Simultaneously, in a separate flask a mixture of hydroxylamine hydrochloride (2.0 gin, 29 mmnol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at OC for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of CH₂C₁₂ and added slowly to the hydroxylamine at O° C. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was extracted with chloroform and washed well with water. The product obtained was purified by silica gel column chromatography and eluted with chloroform the product 4-(4-Methoxy-benzenesulfonyl)1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a colorless solid. mp 90-95 ° C.; Yield, 1.2 g, 48%; MS: 405 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 3 2.29 (m, 3H), 2.″6-2.79 (m, 2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H), 9.37 (s,lH), 10.53 (s,1H), 11.18 (s,1H).

EXAMPLE 84 4(4-methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)piperidine-4arboxylic acid hydroxyamide

[0436] 2-[(2-Hydroxy-ethyl)(3-methoxy-benzyl)amminolthanol was prepared according to the general method as outlined in example 83. Starting from diethanolainine ( 3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride ( 5 g, 31.9 mmol). Yield 9.28 g, (99%); yellow oil; MS: 226 (M+H).

[0437] 3-Methoxybenzyl-bis-(2-chloro-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 3-Methoxy-benzyl diethanolamine (4.4 g, 20 mmol). Yield 4.5 g (93%); yellow solid mp 86 -88 C; MS: 263. (M+H)⁺.

[0438] 4-(4-Methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 22 mnmol) and bis- (2-chloro ethyl) (3-methoxy-benzyl)amine (8.0 g, 23.5 mmol). Yield 2.4 g (24%); low melting solid; MS: 447.9 (M+H)⁺.

[0439] 4-(4-Methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)piperidineX carboxylic acid ethyl ester (2.4g, 5.36 mmol) dissolve in methanol (30 rnL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 710 mg (32%). white solid mp 199 ° C., MS: 419.9 (M+H)⁺.

[0440] Starting from 4-(4-methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)piperidine-4-carboxylic acid (830 mg, 1.98 mmol) and following the procedure as outlined in example 83, 190 mg of 4-(4-methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)piperidine-4-carboxylic acid hydroxamide was isolated as a white solid. mp 130 ° C.; Yield 20.4%; MS: 435.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 2.24-2.32:(m, 2H), 2.51(d, 2H), 2.73-2.83 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 4.32 (s, 2H), 7.01-7.77 (m,8H), 9.38 (s, 1HO, 10.1 (s, 1H).

EXAMPLE 85 1-(3,4dichlorobenzyl) 4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide

[0441] 2-[(2-Hydroxy-ethyl)(3,4dichloro-benzyl)amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (9.0 g, 46 inmol). Yield 13.8 g (99%); colorless oil; MS: 264.3 (M+H)⁺.

[0442] 3,4-Dichlorobenzyl-bis-(2-chloro-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 3,4-dichlorobenzyl diethanolanmine (10.7 g, 41 mmol). Yield 99%; yellow solid mp 218-220 ° C.; MS: 301.8 (M+H)⁺.

[0443] 1-(3,4-Dichloro-benzyl)4-(methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starung from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (2.9 g, 11 mmol) and 3,4-dichlorobenzyl-bis(2-chloroethyl)amine (3.4 g, 11 mmol). Yield 5.9g (60%); brown oil; MS: 494.5 (M+H)⁺.

[0444] 1-(3,4-Dichloro-benzyl)4-(4-methoxy-benzenesulfulfonyl)piperidine-4-carboxylic acid was prepared starting from 1-(3,4-dichloro-benzyl)4-(methoxy-benzenesulfonyl)piperidineX carboxylic acid ethyl ester (5.0 g, 10 mmol) dissolved in methanol (50 mL), 10 N sodium hydroxide (15 niL) and tetrahydrofuran (75 rnL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.94 g (62%), MS: 458.3 (M+H)⁺.

[0445] Starting from 1 -(3,4-dichlorobenzyl)4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid (2.67g, 5.8 mmol) and following the procedure as outlined in example 83, .2 g of 1-(3,4-dichlorobenzyl) t(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide was isolated as a white solid. mp 192-195 ° C.; Yield 10%; MS 472.9 (M+H)⁺;

[0446]¹H NMR (300 MHz, DMSO-d₆): 3 2.20-2.28 (m, 2H), 2.76-2.79 (m, 2H), 3.43-3.44 (m, 4H), 4.30 (s, 2H), 7.14-7.17 (d, J=.030, 2H), 7.50-7.73 (d,. J=.02,7, 1H), 7.65-7.68 (d, J=.029, 2H), 7.72-7.75 (d, J=.027, 2H), 7.87 (s, 1H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).

EXAMPLE 86 4-4-methoxy-benzenesulfonyl)1-(4methylbenzyl)piperidin n-carboxylic acid hydroxamide

[0447] 2-[(2-Hydroxy-ethyl)(4-methyl-benzyl) amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46 mmol). Yield 9.8 g (99%); MS: 209.9 (M+H)⁺. 4-Methylbenzy]-bis-(2-chloroethyl)amine was prepared according to the general method as outlined in example 83. Starting from 4-methyl-benzyl diethanolamine (6 g, 20 mmol). Yield 5.2 g (84%); yellow solid mp 145-147 ° C.; MS: 245.9 (M+H)⁺.

[0448] 4-(4-Methoxy-benzenesulfonyl) -(4-methyl-benzyl)piperidine-arboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (7.0 g, 27 mmol) and 4-methyl-bis-(2-chloro-ethyl)amine (5.0 g, 17 mmol). Yield 4.64 g (63%); low melting solid; MS: 431.9 (M+H) .

[0449] 4-(4-Methoxy-benzenesulfonyl) 1-(4-methyl-benzyl)piperidineAcarboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (4.3g, 9.9 mmol) dissolve in methanol (30 nL) , 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in is example 83. Yield 1.6 g (40%). white solid mp 207-208 ° C. , MS: 404.3 (M+H)⁺.

[0450] Starting from 4-(4-methoxy-benzenesulfonyl)1-(4-methylbenzyl)piperidineAcarboxylic acid (1.59g, 3.9 mmol) and following the procedure as outlined in example 83, .505 g of 4-(4-methoxy-benzenesulfonyl)1-(4-methylbenzyl)piperidine-4-carboxylic acid hydroxamide was isolated as a white solid. mp 176-177 ° C.; Yield 32%; MS: 419.0 (M+H)⁺; ¹H NMR (300 1MHz, DMSO-d₆): 3 2.24-2.32 (m, 2H), 2.51(t, 3H), 2.73-2.90 (m, 2H), 3.35-3.50 (m, 4H), 3.87 (s, 3H), 4.24 (s, 2H), 7.13-7.17 (d, J.039, 2H), 7.23-7.60 (d, J=.036, 2H), 7.38-7.41 (d, J=.025, 2H), 7.65-7.68 (d, J=.039, 2H).

EXAMPLE 87 4-(4-methoxy-benzene-sulfonyl)1-napthalene-2-yl-methylpiperidine-4arboxylic acid hydroxamide

[0451] 2-[(2-Hydroxy-ethyl)(2-napthyl-2-ylmethyl)amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (6.18 g, 59 mmol) and 2-(bromomethyl)napthalene (10 g, 45 mmol). Yield 12.7 g (96%); yellow solid mp 162-164° C.; MS: 246.0 (M+H)⁺.

[0452] 2-Napthyl-2-ylmethyl-bis-(2-chloro-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 2-napthyl-ylmethyl-diethanol amine (10 g, 36 mmol). Yield 9.1 g (79%); brown solid mp 124-126 ° C.; MS: 281.9 (M+H)⁺.

[0453] 4-(4-Methoxy-benzenesulfonyl)napthalene-ylmethyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (8.4 g, 32 mmol) and 1-napthalene-ylmethyl-bis-(2-chloro-ethyl)amine ((8.6 g, 27 mmol). Yield 6.5 g (52%); low melting solid; MS: 440.0 (M+H)⁺.

[0454] 4-(4-M ethoxy-benzenesulfonyl) 1 -napthalene-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)napthalene-ylmethyl-piperidineffi carboxylic acid ethyl ester (6.3g, 13 mmol) dissolved in methanol (30 mL), 10 N sodium hydroxide (30 mL) and tetrahydrofuiran (30 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.3 g (36%). yellow solid mp 226-228 ° C., MS: 440.0 (M+H +.

[0455] Starting from 4-(4-methoxy-benzenesulfonyl)1-napthalene-2-yl-methylpiperidine-4-carboxylic acid (2.18g, 5.0 mmol) and following the procedure as outlined in example 83, .753 g of4-(4-methoxy-benzene-sulfonyl) 1 -napthalene-2-yl-methylpiperidine~carboxylic acid hydroxamide was isolated as a off white solid. mp 168-170 ° C.; Yield 31%; MS 455.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 6 2.29-2.33 (m, 2H), 2.86-2.89(m, 2H), 3.42-3.46 (m, 4H), 3.85 (s, 3H), 4.46 (s, 2H), 7.13-7.16 (d, J=.030, 2H), 7.56-7.64 (m, 3H), 7.65-7.68 (d, J=.030, 2H), 7.98-8.00 (m, 3H), 8.21 (s, 1H), 10.70 (s, 1H), 11.20 (s,iH).

EXAMPLE 88 1-Biphenyl~ylmelyl4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide

[0456] 2-[(2-Hydroxy-ethyl)1-biphenylylmethyl))amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanol amine (5.2 g, 49 mmol) and 4-(chloromethyl)biphenyl (10 g, 49 mmol). Yield 9.98 g (66%); white solid mp 160-162 IC; MS: 271.9 (M+H)⁺. This was converted to the dichloride as outlined in example 83

[0457] 1-Biphenyl-4-ylmethyl4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (2.85 g, 11 mnol) and 1-biphenyl ylmethyl-bis-(2chloroethyl)amine (3.4 g, 11 Immol). Yield 2.1 g, (39%); beige solid, mp 176-178° C., MS: 494.1 (M+H)⁺.

[0458] 1-Biphenyl-4-ylmethyl(4-methoxy-benzenesulfonyl)piperidineA4-carboxylic acid was prepared starting from 1-biphenyl-4-ylmethyl-(4-methoxy-benzenesulfonyl)piperidine-4 carboxylic acid ethyl ester (5.7g, 12 mnmol) dissolved in ethanol (20 mL), tetrahydrofilr (20 mL) and 10 N sodium hydroxide (10 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.1g (39%) MS: 465.8 (M+H)⁺.

[0459] Starting from 1-biphenyl4-ylmethyl4-(4-methoxy-benzenesulfonyl)piperidine-4carboxyjic acid (1.Og, 2.2 mmol and following the procedure as outlined in example 83, .132g of 1-biphenyl4fylmethyl4-(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid hydroxamide was isolated as a tan solid. mp168 IC; Yield 20%; MS: 440.9 (M+H)'; ¹H NMR (300 Mh, DMSO-d₆): 6 2.30-2.35 (m, 2H), 2.83-2.87 (m, 2H), 3.35-3.5 (m, 4H), 3.87 (s, 3H), 7.15-7.721 (d, J=.059 Hz, 2H), 7.49-7.65 (m, 5H), 7.68-7.74′(d, J=.06 Hz, 2H), 9.3 (s, 1H), 10.3 (s, 1H), 11.15 (s, 1H).

EXAMPLE 89 4-(4-methoxy-benzene-sulfonyl)1-(3-methyl-but-2-enyl)piperidine~carboxylic acid hydroxamide

[0460] 2-[(2-Hydroxy-ethyl)1-(3-methyl-but-2-enyl)amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanol amine (4.1 g, 39 mmol) and 4-bromo-2-methyl-butene (6.0 g, 40 mmol). Yield ( 98%); brown oil; MS: 173.8 (M+H)⁺. 1-(3-methyl-but-2-enyl)]-bis-(2-chloro-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-hydroxythyl)1-(3-methyl-but-2-enyl)amino]-ethanol (10.4g, 50 mmol). Yield 10.5g (99%); brown solid; MS: 210.3 (M+H)

[0461] 4-(4-Methoxy-benzenesulfonyl)1-(3-methyl-but-2-enyl)piperidine~carboxylic acid ethyl ester was prepared according to the general method as outlined in example 1. Starting from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (11.32 g, 44 mmol) and 3-methyl-but-2-enyl)bis-(2chloroethyl)amine ( 10.4 g, 50 mmol). Yield 6.2 g (36%); brown oil; MS: 395.6 (M+H)⁺.

[0462] 4-(4-Methoxy-benzenesulfonyl)13-methyl-but-2-enyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)1-3-methyl-but-2-enyl)piperidine carboxylic acid ethyl ester (6.2g, 16 mmol) dissolved in ethanol (15 nrL), 10 N sodium hydroxide (10 nL) and tetrahydrofiran (75 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (21%). brown solid mp 196-197 ° C., MS: 367.9 (M+H) .

[0463] Starting from 4-(4-methoxy-benzenesulfonyl) 1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid (1.0 g. 3.0 mmol) and following the procedure as outlined in example 83, .110 mg of 4-(4-methoxy-benzene-sulfonyl) 1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide was isolated as a yellow solid. mp 142-145 ° C.; Yield 12%; MS: 382.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 1.67 (s, 3H), 1.79 (s, 3H), 2.18-2.23 (m, 2H), 2.66-2.73 (m, 2 H), 3.37-3.46 (m, 2H), 3.67-3.69 (m, 2H), 5.19-5.24 (m, 1H), 7.15-7.18 (d, J=.03, 2H), 7.67-7.70 (d, J=.030, 2H), 9.34 (s, 1H), 9.88 (s, 1H),. 11.15 (s, 1H).

EXAMPLE 90 1-(4-Bromo-benzyl)D(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

[0464] 2-[(4-Bromobenzyl)(2-hydroxy-ethyl)amino1-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolaniine (22.5 g, 150 mmol). and 4-bromobenzyl bromide (25 g, 100 mmol). Yield 33.66g, (99%); yellow oil; MS: 273.8 (M+H) .

[0465] (4-Bromo-benzyl)bis-(2-chloro-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 2-[(4-bromobenzyl)(2-hydroxyethyl)amnino]-ethanol (33.28 g, 122 mmol). Yield 47 g, (99%); brown solid; mp 125 ° C.; MS: 309.8 (M+H)⁺. 1-(4-Bromo-benzyl)4-(4-methdxy-benzenesulfonyl)piperidine-4arboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (8.6 g, 33.5 mmol) and (4bromo-benzyl) bis2chloroethyl)arine (13.3 g, 38.6 mmol). Yield 17 g (44%); brown oil; MS: 497.8 (M+H)⁺.,

[0466] 1-(4-Bromo-benzyl)4-(4-methoxy-benzenesulfonyl)piperidinencarboxylic acid was prepared starting from I-(4-bromo-benzyl)4-(4-methoxy-benzenesulfonyl)piperidine-4 carboxylic acid ethyl ester (16.5 g, 33.3 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.18 g (40%); tan solid; mp 215 ° C.; MS: 469.7 (M+H)⁺.

[0467] Starting from 1-(4-Bromo-benzyl)444-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid (1.95 g, 4.2 mmol) and following the procedure as outlined in example 83, 1.29 g of 1-(4-bromo-benzyl)4-(4-methoxy-benzenesulfonyl)piperidineAcarboxylic acid hydroxyamide was isolated as an off white solid. Yield 60%; mp 180 AC; MS: 484.7 (M+H)⁺; ¹H NMR (300 5 MHz, DMSO-d₆): 6 2.18-2.29 (m, 2H), 2.46 (d, 2H), 2.74-2.89 (m, 2H), 3.39 (d, 2H), 3.87 (s, 3H), 4.28 (s, 2H), 7.18 (d, J=17 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.65- 7.68 (m, 4H), 9.37 (s, 1H), 10.5 (s, 1H).

EXAMPLE 91 4-(4-methoxy-benzenesulfonyl)1-(3-phenyl-propyl)piperidine-4-carboxylic acid hydroxyanmide

[0468] 2-((2-Hydroxyethyl)(3-phenyl-propyl)amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.8 g, 151 mmol). and 1-bromo-3-phenylpropane (20 g, 101 mmol). Yield 21.31 g, (95%); yellow oil; MS: 223.9 (M+H)⁺.

[0469] Bis-(2-Chloroethyl)(3-phenyl-propyl)amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-hydroxy-ethyl)(3-phenyl-propyl)amino]-ethanol (20.32 g, 90.7 mmol). Yield 24.9 g (92%); brown oil; MS: 259.8 (M+H)⁺.

[0470] 4-(4-Methoxy-benzenesulfonyl)1-(3-phenyl-propyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (12 g, 46.5 mmol) and bis-2-chloro-ethyl)(3-phenyl-propyl)amine (24.8 g, 93.8 mmol). Yield 11.24 g (54%); brown oil; MS: 446 (M+H)⁺.

[0471] 4-(4-Methoxy-benzenesulfonyl)1 -3-phenyl-propyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl) l3-phenyl-propyl)piperidineX carboxylic acid ethyl ester (10.74 g, 24.13 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.67 g (47%); off white powder; mp 203 ° C.; MS: 418.2 (M+H)⁺.

[0472] Starting from 4-(4-methoxy-benzenesulfonyl)1-(3-phenyl-propyl)piperidine~carboxylic acid (4.37 g, 10.4 mmol) and foflowing the procedure as outlined in example 83, 1.64 g of 4-(4-methoxy-benzenesulfonyl)1-3-phenyl-propyl)piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 37%; mp 143 ° C.; MS: 432.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 1.92-1.97 (m, 2H), 2.18-2.29 (m, 2H), 2.47 (d, 2H), 2.58 (t, J=7.7 Hz, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 7.15-7.30 (m, 7 H), 7.68, (d, J=9 Hz, 2H), 9.3 (s, 1H), 10.1 (s, 1H).

EXAMPLE 92 1-Tert-butyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamnide

[0473] tert-Butyl-bis-(2-chloro-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 1-tert-butyl-diethanolamine (6 g, 37.2 mmol). Yield 11.15 g, (99%); white solid; MS: 197.8 (M+H)⁺.

[0474] 1-tert-Butyl(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (10 g, 38.76 mmol) and tert-butyl-bis-(2-chloro-ethyl)amine (5.25 g, 22.53 mmol). Yield 5.37 g, (62%); brown oil; MS: 384 (M+H)⁺.

[0475] 1-tert-Butyl4-(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid was prepared starting from 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (5.37 g 14 mmol) dissolved in methanol (300 ml) and 10 N NaOH (23 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.52 g (30.6%); white powder; mp 204 ° C.; MS: 356 (M+H)⁺.

[0476] Starting from 1-tert-butyl(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid (320 mg, 0.9 mmol) and following the procedure as outlined in example 83, 190 mg of 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide was isolated as a green solid. Yield 52%; mp 40 ° C.; MS: 371.1 (M+H)⁺; ¹H NMR (300 MD, DMSO d6): 8 1.29 (s, 9H), 1.54 (in, 2H), 1.66 (m, 2H), 2.39 (m, 2H), 2.98 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H), 7.67 (d, 2H).

EXAMPLE 93 1-Butyl(4-methoxy-benzenesulfonyl)piperidinefarboxylic acid hydroxyamide

[0477] Butyl-bis-(2-chloro-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from N-butyldiethanolamine (6 g, 37.2 mmol). Yield 11.3 g, (99%); white powder, mp 165 ° C.; MS: 197.9 (M+H)⁺. 1-Butyl4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5 g, 19.38 mmol) and butyl-bis-(2-chloro-ethyl)amine (4.52 g, 19.38 mmol). Yield 6.86 ;, (93%); brown oil; MS: 384 (M+H)⁺.

[0478] 1-Butyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid was prepared starting from 1-butyl~(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (6.42 g 16.8 imol) dissolved in methanol (200 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.6 g (27%); white powder; mp 206 C; MS: 356.4 (M+H)⁺.

[0479] Starting from 1-butyl-4-(4-methoxy-benzenesulfonyl)piperidinencarboxylic acid (1.51 g, 4.3 mmol) and following the procedure as outlined in example 83, 200 mg of 1-butyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 9.3%; mp 75 ° C.; MS: 371.1 (M+H)⁺; ¹H NMR (300 MHz, DMSO-dd: 3 0.87 (t, J=7.2 Hz, 3H), 1.27 (m, 2H), 1.59 (m, 2H), 2.27 (m, 2H), 2.45 (m, 2H), 2.50 (m, 2H), 2.65 (m, 2H), 2.97 (m, 2H) 3.88 (s, 3H), 7.18 (d, 2H), 7.69 (d, 2H).

EXAMPLe 94 1-Cyclooctyl+(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid hydroxyamide

[0480] Cyclooctyl-bis-(2-chloro-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from N-cyclooctyldiethanolaminne (6 g, 28 mmol). Yield 10 g, (99%); off white solid; mp 158 ° C.; MS: 251.9 (M+')⁺.

[0481] 1-Cyclooctyl4-(4-methoxy-benzenesulfonyl)piperidinencarboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5 g, 19.4 mmol) and cyclooctyl-bis-(2-chloro-ethyl)amine (5.57 g, 19.4 inmol). Yield 8.2 g, (96%); brown oil; MS: 438 (M+H)I.

[0482] 1-Cyclooctyl4-(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid was prepared starting from 1yclooctyl~(4-methoxy-benzenesulfonyl)piperidine oxylic acid ethyl ester (8 g, 183 mmol) dissolved in methanol (200 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.36 g (32%); white powder; mp 180 ° C.; MS: 410 (M+H)⁺.

[0483] Starting from I-Cyclooctyl~(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid (2.26 g, 5.53 mmol) and following the procedure as outlined in example 83, 570 mg of 1-cyclooctyl(4-imethoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide was isolated as a white powder. Yield 22%; mp >200 CC; MS: 425 (M+H)⁺; tH iNiIR (300 M DMSO-d₆): 5 1.42-1.66 (m, 14H), 1.83 (m, 2H), 2.33 (m, 2H), 2.67 (m, 2H), 3.30-3.51 (m, 3H) 3.88 (s, 3H) 7.17 (d, 2H), 7.66 (d, 2H).

EXAMPLE 95 1-Ethyl(4-imethoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

[0484] 1-Ethyl4-(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 11.6 mmol) and ethyl-bis-(2-chloro-ethyl)amine (2.39g, 11.6 mmol). Yield 3.09 g, (75%); low melting brown solid; MS: 356 (M+H)⁺.

[0485] 1-Ethyl4-(4-methoxy-benzenesulfonyl)piperidine-4fcarboxylic acid was prepared starting from 1-ethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.29 g (58%); white solid; mp 209° C.; MS: 328 (M+H)⁺.

[0486] Starting from 1-ethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid (1.23 g, 3.76 mnmol) and following the procedure as outlined in example 83, 1.02 g of 1-ethyl-(4-ethoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide was isolated as an off white powder. Yield 80%; mp 85 ° C.; MS: 343 (M+H)⁺; tH NMR (300 M}z, DMSOd₆): 3 0.926 (t, J=7.1 Hz, 3H), 1.68-1.89 (m, 4H), 2.05-2.24 (m, 4H), 2.73 (q, 2H), 3.85 (s, 3H), 7.07 (d, 2H), 7.64 (d, 2H).

EXAMPLE 96 1-Isopropyl444-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

[0487] Isopropyl4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.7 g, 22.2 mmol) and isopropyl-bis-(2-chloro-ethyl)amine (4.9 g, 22.2 mmol). Yield 5.64 g, (68%); low melting brown solid; MS: 370 (M+H).

[0488] 1-Isopropyl4-(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid was prepared starting from 1-isopropyl4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (5.6 g, 15.2 mmol) dissolved in methanol (75 ml) and 10 N NaOH (25 mnl). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.18 g (42%); white powder; mp 204 ° C.; MS: 341.9 (M+H)⁺.

[0489] Starting from 1-isopropyl4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid (2.13 g, 6.25 mmol) and following the procedure as outlined in exam nple 83, 590 mg of 1-isopropyl-4-(4-methoxy-benzenesulfonyl)piperidine-4arboxylic acid hydroxyamide was isolated as a white powder. Yield 2.4%; mp 75 ° C.; MS: 357 (M+H)⁺; ¹H NMR (300 MI, DMSO-dd: 3 1.21 (d, J=6.6 Hz, 6H), 2.33-3.53 (m, 9H), 3.88 (s, 3H), 7.16 (d, 2H), 7.66 (d, 2H).

EXAMPLE 97 1-Methyl-4-(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid hydroxyamide

[0490] 1-Methyl-4-(4-methoxy-benzenesulfonyl)piperidinencarboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 11.6 mmol) and methyl-bis-(2chloro-ethyl) amine (2.2g, 11.6 mmol). Yield 3.09 g, (75%); low melting brown solid; MS: 342 (M+H)⁺.

[0491] 1-Methyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid was prepared starting from 1-methyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (8.7 g, 25.6 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.23 g (41%); white solid; mp 204° C.; MS: 313.9 (M+H)⁺.

[0492] Starting from 1-methyl-4-(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid (2.0 g, 638 mmol) and following the procedure as outlined in example 83, 1.10 g of 1-methyl-4-(4 methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide was isolated as a yellow powder. Yield 53%; mp 89 ° C.; MS: 329 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 1.67-1.76 (m, 2H), 1.85-1.96 (m, 2H), 2.05 (s, 3H), 2.17 (d, J=11.4 Hz, 2H), 2.57 (d, J=10.4 Hz, 2H) 3.83 (s, 3H), 7.02 (d, 2H), 7.62 (d, 2H).

EXAMPLE 98 1-Benzyl-4-(4butoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

[0493] 1 -Benzyl-4-(4butoxy-benzenesulfonyl)piperidine~carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from SQbutoxy-benzenesulfonyl) acetic acid ethyl ester (6 g, 20 mmol) and bis-(2-chloro-ethyl)benzylamine (10 g, 30 mmol). Yield 5.15 g (56%); yellow oil; MS: 460 (M+H)⁺. 1-Benzyl-4-(4butoxy-benzenesulfonyl)piperidine~carboxylic acid was prepared starting from 1-benzyl4-(4butoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (5.1 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.66 g (56%); off white solid; mp 210 ° C.; MS: 432 (M+H)⁺.

[0494] Starting from 1-benzyl4-(4butoxy-benzenesulfonyl)piperidine~carboxylic acid (2.61 g, 6.06 mmol) and following the procedure as outlined in example 83, 860 mg of I-benzyl4-(4-butoxy-benzenesulfonyl)piperidineAcarboxylic acid hydroxyamide was isolated as an off white powder. Yield 32%; mp 144 ° C.; MS: 446.9 (M+H)⁺; ¹H NMR (300 MH, DMSO-d): 8 0.94 (t, J=7.3 Hz, 3H), l.44 (q, J=7.5 Hz, 2H), 1.70 (q, 2H), 2.28-2.32 (m, 2H), 2.50 (d, 2H), 2.74-2.83 (m, 2H), 3.35 (d, 2H), 4.08 (t, J=6.3 Hz, 2H), 4.34 (s, 2H), 7.13 (d, J =8.7, 2H), 7.45 (s, 3H), 7.54 (s, 2H), 7.74 (d, J=8.7, 2H), 9.35 (s, 1H), 10.7 (s, 1H).

EXAMPLE 99 1-(4-Fluoro-benzyl) (4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

[0495] 1-(4-Fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (18.8 g, 72.8 mmol) and (4-fluoro-benzyl) bis-(2-chloro-ethyl)amine (20.8 g, 73 mmol). Yield 25 g (79%); brown oil; MS: 436.9 (M+H) .

[0496] 1-(4-Fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid was prepared starting from 1-(4-fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)piperidinef carboxylic acid ethyl ester (17.4 g, 40 nmnol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 10.8 g (66%); colorlesssolid; mp 154 ° C.; MS: 408 (M+H)⁺.

[0497] Starting from 1-(4-Fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)piperidine-4arboxylic acid (8.14 g, 20 mmol) and following the procedure as outlined in example 83, 4.3 g of 1-(4-fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 51%; mp 176-178 ° C.; MS: 484.7 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 8 2.12-2.20 (m, 2H), 2.64-2.79 (m, 2H), 3.32-3.45 (m, 4H), 3.87 (s, 3H), 4.31 (s, 2H), 7.14-7.19 (d, J=17 Hz, 2H), 7.27-7.33 (d, J=8.1 Hz, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H), 9.38 (s, 1H), 9.75 (s, 1H).

EXAMPLE 100 1-(4-Fluoro-benzyl)4-(4-butoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

[0498] 1-(4-Fluoro-benzyl)4-(4-butoxy-benzenesulfonyl)piperidinencarboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (6 g, 20 mmol) and (4-fluoro-benzyl)bis-(2-chloro-ethyl)amine (5.73 g, 20 mmol). Yield 8.2 g (86%); yellow oil; MS: 478 (M+H)⁺.

[0499] 1-(4-Fluoro-benzyl)(4butoxy-bezenesulfonyl)piperidine-4-carboxylic acid was prepared starting from I-(4-Fluoro-benzyl)4-(4-butoxy-benzenesulfonyl)piperdinecarboxylic acid ethyl ester (4.77 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (79%); off white solid; mp 114 ° C.; MS: 450 (M+H)⁺.

[0500] Starting from 1-(4Fluoro-benzyl)(butoxy-benzenesulfonyl-piperidine-4arboxylic acid (2.24 g, 5.0 mmol) and following the procedure as outlined in example 83, 200 mg of 1-(* Fluoro-benzyl)4-(4butoxy-benzenesulfonyl)piperidinetcarboxylic acid hydroxyamide was isolated as an off white powder. Yield 9%; mp 112 ° C.; MS: 465.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): 8 0.94 (t, J=7.3 Hz, 3H), 1.35-1.50 (m, 2H), 1.68-1.77 (m, 2H), 2.20-2.28 (m, 2H), 2.66-2.77 (m, 2H), 3.77-3.78 (m, 4H), 4.06-4.10 (m, 2H), 4.19 (s, 2H), 7.14-7.19 (d, J=8.7, 2H), 7.27-7.33 (d, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H), 9.34 (s. 1H), 10.55 (s, 1H).

EXAMPLE 101 (4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine~carboxylic acid hydroxyamide

[0501] 2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (12.0 g, 114 mmol) and 4-methoxybenzyl chloride ( 14.2 g, 100 mmol). Yield 17.5 g, (77%); yellow oil; MS: 226 (M+H).

[0502] 4-Methoxybenzyl-bis-(2-chloro-ethyl)amine was prepared accordinag to the general method as outlined in example 83. Starting from 4-Methoxy-benzyl diethanolamine (10 g, 44 mmol). Yield 10 g (75%); yellow solid mp 55 C; MS: 263.1 (M+)⁺.

[0503] 4-(4-Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4 (methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) and bis- (2-chloro ethyl) (4-methoxy-benzyl)amine (7.0 g, 22 mmol). Yield 5.0 g (56%); low melting solid; MS: 448.5 (M+H)⁺.

[0504] 4-(4-Methoxy-benzenesulfonyl) 1-(4-methoxy-benzyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)1-(4-methoxy-benzyl)piperidine-4 carboxylic acid ethyl ester (4.2g, 10 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofbran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (71 S). white solid mp 190 IC, MS: 420.4 (M+H)⁺.

[0505] Starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylic acid (2.0 g, 4.7 mmol) and following the procedure as outlined in example 83, 1.2 g of 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidineAcarboxylic acid hydroxamide was isolated as a white solid. mp 175° C. (HCl); Yield: 1.2 g, 59%; MS: 433.0 (M+H)⁺; ¹H NoM (300 MHz, DMSO-d6): 5 1.8 (m, 4H), 2.3(m, 2H), 2.73 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s,3H), 6.87 ( d, 2H), 7.11 (d, 2H), 7.21 (d, 2H), 7.65 (d, 2H), 9.2 (bs, 1H), 10.9 (bs, 1H).

EXAMPLE 102 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxyllc acid hydroxyamide

[0506] 2-{(2-Hydroxy-ethyl)[2-(4-methoxy-phenyl)ethyl]-amino }-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (10.0 g, excess). and 1-(2-chloroethyl)4-methoxybenzene (8.5 g, 50 mmol). Yield 1 -1 g, (92%); yellow oil; MS: 240 (M+H)⁺.

[0507] The corresponding dichloride, bis-(²-chloro-ethyl)(4-methoxyphenyl-2-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 2-{(2-hydroxy-ethyl)[2-(4-methoxy-phenyl)ethyl]-amino }-ethanol (10 g, 41.8 mmol). Yield II g (95%); brown oil; MS: 277.2 (M+H)⁺.

[0508] 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)ethyl]-piperidine~carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mrmo1) and bis-(2-chloro-ethyl)(4-methoxyphenyl-2-ethyl)amine (6.4 g, 20 mmol). Yield 6.0 g (65%); brown oil; MS: 462.5 (M+H)⁺.

[0509] 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)ethyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)ethyl]-piperidine-4-carboxylic acid ethyl ester (5.0 as 10.8 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 0 (85%); off white powder; mp 205 ° C.; MS: 434.5 (M+H)⁺.

[0510] Starting from 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)ethyl]-piperidineX carboxylic acid (1.5 g, 3.46 mmol) and following the procedure as outlined in example 83, 900 mig of 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)ethyl1-piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 58%; mp 206 ° C. (HCI); MS: 449.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d,): 5 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m,4H), 3.60 (d, J=12.3 Hz, 2H), 3.77 (s, 3H),3.99 (s, 3H), 6.9 (d, 2 H), 7.1- 7.25, (q, 4H), 7.7 (d, 2H), 9.3 (s, 1H), 10.6 (s, 1H).

EXAMPLE 103 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)piperidine-4-carboxylic acid hydroxyamide

[0511] 2-[(2-Hydroxy-ethyl)(2-phenyl-ethyl)amino]-ethanol was prepared according to the general method as outlined in example 1. Starting from diethanolamine (6.0 g, 57). and 2-bromo-ethylbenzene (9.0 g, 48.3 mmol). Yield 9 g, (90%); yellow oil; MS: 210 (M+H)⁺.

[0512] Bis-(2-Chloro-ethyl)(2-phenyl-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-Hydroxy-ethyl)(2-phenyl-ethyl)amino]-ethanol (8.5 g, 40.6 mmol). Yield 11 g (95%); brown oil; IMS: 247.1 (M+H)⁺.

[0513] 4-4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mmol) and bis-(2-chloro-ethyl)(2-phenyl-ethyl)amine (5.6 g, 20 mmol). Yield 5.5 g (63%); brown oil; MS: 432.5 (M+H)⁺.

[0514] 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl) 1 -(2-phenyl-ethyl)piperidinencarboxylic acid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.0 g (72%); off white powder, mp 208 ° C.; MS: 404.5 (M+H)⁺.

[0515] Starting from 4 methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)piperidine-4-carboxylic acid (1.5 g, 3.7 minol) and following the procedure as outlined in example 83, 900 mg of 4-(4methoxy-benzenesulfonyl)-1-(2-phenylethyl)piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 58%; mp 205 ° C. (HCI); MS: 419.4 (M+H)⁺; ¹H NMR (300 MIz, DMSO-d₆): 5 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 2.95 (mn, 2H), 3.25 (m, 2H), 3.4 (m,4H), 3.9 (s, 3H),7.22 - 7.8 (m, 9H), 10.6 (s, 1H), 11.2 (bs, 1H).

EXAMPLE 104 4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperdine4-carboxylic acid hydroxyamide

[0516] 4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine~carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(n-Butoxy-benzenesulfonyl)acetic acid ethyl ester (2.5 g, 10 nmmol) and bis- (2-chloro ethyl)(4-methoxy-benzyl)amine (3.0 g, 10 mmol). Yield 3.5 g (71%); low melting solid; MS: 490.5 (M+H)⁺.

[0517] 4-(4-n-Butoxy-benzenesulfonyl) 1-(methoxy-benzyl)piperidine~carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4f carboxylic acid ethyl ester (3.0g, 6.1 nmmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuiran (20 mTL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (53%). white solid mp 207 C, MS: 462.5 (M+H)⁺.

[0518] Starting from 4-(4n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine1arboxylic acid (1.0 g, 2.1 minol) and following the procedure as outlined in example 83, 1.2 g of 4-(4-Butoxy-benzenesulfonyl) 1 -(4-methoxy-benzyl)piperidine-4-carboxylic acid hydroxamide was isolated as a white solid. mp 173 ° C. (HC₁); Yield: 800 mog, 77%; MS:

[0519] 477.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-dd: 8 0.9 (t, 3H), 1.4 (m, 2H), 1.7 (m,2H), 2.3 (m, 2H), 2.5 (m, 2H), 2.7 (m, 2H), 3.3 (m, 2H), 3.5(m, 2H), 4.1 (t, 2H), 4.3 (m, 2H), 6.97 ( d, 2H), 7.14 (d, 2H), 7.48 (d, 2H), 7.7 (d, 2H), 9.4 (bs, 1H), 10.9 (bs, 1H).

EXAMPLE 105 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)piperdined arboxylic acid hydroxyamide

[0520] 2-[(2-Hydroxy-ethyl)(3-phenoxy-propyl)amno]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.8 g, 151 mmol). and 3-Phenoxypropyl bromide (21.5 g, 100 mmol). Yield 21.31 g, (95%); yellow oil; MS: 238.1 (M+H)⁺.

[0521] Bis-(2-Chloro-ethyl)(3-phenoxy-propyl)amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-hydroxy-ethyl)(3-phenoxy-propyl)amino]-ethanol (20.0 g, 84 mmol). Yield 24.0 g (91%); brown oil; MS: 277.8 (M+H)⁺.

[0522] 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.2 g, 20 mmol) and bis-(2-chloro-ethyl) (3-phenoxy-propyl)armine (7.0 g 22 mmol). Yield 6.5 g (70%); brown oil; MS: 462.5 (M+H)⁺.

[0523] 4-(4-Methoxy-benrenesulfonyl)-1-(3-phenoxy-propyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl) 1 -(3-phenoxy-propyl)piperidine-4 carboxylic acid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 3:1 and I0 N NaOH (40 ml). The resulting reaction mixture was worked up as'outlined in example 83. Yield 3.0 g (75%); off white powder; mp 195 ° C.; MS: 434.5 (M+H)⁺.

[0524] Starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)piperidine-4-carboxylic acid (2.5 g, 5.77 mmol) and following the procedure as outlined in example 83, 1.2 g of 4-(4-methoxy-benzenesulfonyl) 1 -(3-phenoxy-propyl)piperidine~carboxylic acid hydroxyamide was isolated as an off white solid Yield 46%; mp 101 ° C.; MS: 448.5 (M+H)⁺; ¹H NIMR (300 MHz, DMSO-d6): 5 2.18 (m, 2H), 2.3 (m, 21), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (m 2H), 3.87 (s, 31), 4.01 (t, 2H), 6.9 - 7.7 (m, 9H), 9.33 (bs, 1H), 10.28 (bs, 1-1H).

EXAMPLE 106 4-(4n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)piperidine~carboxylic acid hydroxyamide

[0525] 4(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (3.0 g, 10 mmol) and bis-(2chloro-ethyl) (3-phenoxy-propyl)amine (3.0 g, 11 Immol). Yield 4.5 g (89%); brown oil; MS: 504.6 (M+H)⁺.

[0526] 4-(4-n-Butoxy-benzenesulfonyi)-1-(3-phenoxy-propyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)piperidine-4-carboxylic acid ethyl ester (4.0 g, 7.9 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (79%); off white powder; mp 191 ° C.; MS: 476.5 (i+H)'.

[0527] Starting from 4-(4n-butoxy-benzenesulfonyl) 1-(3-phenoxy-propyl)piperidinefcarboxylic acid (700 mg, 1.4 imol) and following the procedure as outlined in example 83, 300 mg of 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)piperidinencarboxylic acid hydroxyamide was isolated as an off white solid. Yield 43%; mp 84 ° C.; MS: 491.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 6 0.9 (t, 3H), 1.5 (m, 2H),1.8 (m, 2H), 2.18 (m, 2H), 2.3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.2 (m, 2H), 3.40 (m 6H), 3.97 (t, 2H), 4.1 (t, 2H), 6.9 - 7.7 (m, 9H), 10.7 (bs, 1H), 11.28 (bs, 1H).

EXAMPLE 107 4(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)piperidine-4-carboxylic acid hydroxyamide

[0528] 2-[(2-Hydroxy-ethyl)(2-phenoxy-ethyl)amino]thanol was prepared according to the general method as outlined in example 83. Starting from diethanolainine (15.0 g, 150). and 2-chloro-phenetol (15.6 g, 100 mmol). Yield 18 g, (80%); Colorless oil; MS: 226 (M+H)⁺.

[0529] Bis2-Chloro-ethyl)(2-phenoxy-ethyl)amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-Hydroxy-ethyl)(2-phenoxy-ethyl)amino] ethanol (20.0 g, 88.8 mmol). Yield 25 g (94%); brown oil; MS: 263.1 (M+H)'.

[0530] 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mnmol) and bis-(2-chloro-ethyl)(2-phenoxy-ethyl)amine (6.0 g, 20 mmol). Yield 5.8 g (64%); brown oil; MS: 448.5 (M+H)⁺.

[0531] 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)piperidinew carboxylic acid ethyl ester (5.0 g, 11.1 Inmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (63%); off white powder; mp 235 ° C.; MS: 420.5 (M+H)⁺.

[0532] Starting from 4-(methoxy-benzenesulfonyl) 1-(2-phenoxy-ethyl)piperidineAcarboxylic acid (2.5 g, 5.9 mmol) and following the procedure as outlined in example 83, 1.3 g of 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 50%; mp 168-172 ° C. (HCI); MS: 435.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 6 2.3 (m, 2H), 2.5 (m, 2H), 2.9 (m, 2H), 3.4 (m, 4H), 3.5 (m, 2H), 3.7 (m,2H), 3.9 (s, 3H), 4.4 (m, 2H), 6.9 - 7.8 (m, 9H), 9.3 (s, 1H), 10.2 (bs, 1H), 11.3 (s, 1H).

EXAMPLE 108 4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)piperidine-4-carboxylic acid hydroxyamide

[0533] 4-(4Butoxy-benzenesulfonyl)-1-(2-phenoxyethyl)piperidine~carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (2.5 a, 10 mmol) and bis-(2-chloro-ethyl)(2-phenoxy-ethyl)amine (2.98 g, 10 mmol). Yield 3.0 g (69%); brown oil; MS: 490.6 (M+H)⁺.

[0534] 4-(⁴n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)piperidine~carboxylic acid was prepared starting from 4-(4-n-butoxy-benzenesulfonyl)-1 -(2-phenyl-ethoxy)piperidine-4 carboxylic acid ethyl ester (2.5 g, 5.76 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (56%); off white powder, mp 204 ° C.; MS: 462.5 (M+H)⁺.

[0535] Starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)piperidine-4-carboxylic acid (1.0 g, 2.16 mmol) and following the procedure as outlined in example 83, 600 mg of 4-(4-butoxy-benzenesulfonyl)-1-(2-phenoxyethyl)piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 58%; mp 112 ° C. (HCI); MS: 477.4 (M+H)⁺; ¹H NMR (300 MIz, DMSO-dd: 3 0.942 (t, 3H), 1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 2.5 (m, 4H), 2.8 (m, 2H), 2.9-3.4 (m, 4H), 3.3 (m, 4H), 4.2 (t, 2H), 4.4 (m, 2H), 6.9 - 7.7 (m, 9H), 9.4 (s, 1H), 10.5 (bs, 1H), 11.3 (s, 1H).

EXAMPLE 109 4-(4-Methoxy-benzenesulfonyl) 1-4-(2-piperidin- 1 -yl-ethoxy)benzyl]-piperidin carboxylic acid hydroxyamide

[0536] Bis-(2-chloro-ethyl)[4-(2-piperidin-1-yl-ethoxy)benzyl]-amine was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.0 g, 150). and 4-(2-piperidin-1-yl-ethoxy)benzyl chloride (5.9 g, 20 mmol). Yield 5.5 g, (85%); Brown semi-solid; MS: 323 (M+H)⁺.

[0537] Bis-(2-choro-ethyl)[4-(2-piperidin-1-yl-ethoxy)benzyl]-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-Hydroxy-ethyl) (4-(2-piperidin-1-yl-ethoxy)benzyl]-amine (3.22 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H)⁺.

[0538] 4-(4-Methoxy-benzenesulfonyl) 1 -[4-(2-piperidin- 1 -yl-ethox)benzyl]-piperidin ecarboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mmol) and Bis-(2-chloroethyl)[4-(2-piperidin-1-yl-ethoxy)benzyl]-amine (8.6 g, 20 mmol). Yield 6.0 g (55%); brown oil; MS: 545.7 (M+H)⁺.

[0539] 4-(4-Methoxy-benzenesulfonyl)-1 -[4-(2-piperidin- 1-yl-ethoxy)benzyl]-pipendine4 carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl) 1-[(2-piperidin-1-yl-ethoxy)benzyl]-piperidine-4-carboxylic acid ethyl ester (5.4 g, 10 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (77%); off white powder; mp 174 ° C.; MS: 517.6 (M+H)⁺.

[0540] Starting from 4-(4-Methoxy-benzenesulfonyl) 1 -[4-(2-pipeddin- 1 -yl-ethoxy)benzyl]-piperidin e-4-carboxylic acid (3.5 g, 6.78 mnimol) and following the procedure as outlined in example 83,1.8 g of 4-(4-Methoxy-benzenesulfonyl) 1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-piperidin e-4-carboxylic acid hydroxy amide was isolated as an pale yellow solid. Yield 49%; mp 114 OC (HCl); MS: 532 (M+H)'; ¹H NoM (300 MD, DMSO-dd: 3 1.41.6 (m, 4H), 1.9 (m, 2H), s 2.3 (m, 2H), 2.8 (m, 2H), 3.4 (m, 4H), 3.9 (s, 3H), 4.2 (m, 1H), 6.9 - 7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, lH).

EXAMPLE 110 N-Hydroxy-2-(4medioxy-benzenesulfonyl)propionamide

[0541] Step A: Coupling of 2-bromo-propionic acid to hydroxylamine resin. 0-Mediylhydroxylaniine-phenoxymethyl-copoly(styrene-1%divinylbenzene)resin^(t) (2 g, 1.1 meq/g) was placed in a peptide synthesis vessel (Chemglass Inc. Part Number CG-1866) and suspended in DMF (20 mL). 2-Bromopropionic acid (0.6 mL, 3.0 eq.) 1-hydroxybenzotriazole hydrate (HOBt, -1.8 g, 6.0 eq.) and 1,3-diisopropylcarbodiimide (DIC, 1.4 mL, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3×20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling descnbed above was repeated, otherwise the resin was washed with DCM (3×20 nL), MeOH (2×20 mL), and DCM (2×20 mL). (A wash consisted of addition of the solvent and agitation either by nitrogen bubbling or shaking on the orbital shaker for 1-5 minutes, then filtration under. vacuum). The resin was dried iz vacuo at room temperature.

[0542] A sample of resin (5-20 mg) was subjected to cleavage with DCM (0.5 mL) and TFA (0.5 mL) for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (1 x 1 mL). The filtrate and the washing were combined and concentrated in vacuo on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. The product was then characterized by H'NMR, (DMSO d-6) 8 4.54 (q, 1H), 1.83 (d, 3H).

[0543] Step B:Displacement of bromide with 4-methoxybenzenethiol.

[0544] The N-Hydroxy-2-bromo-propionamide resin prepared in Step A (0.35 g, 1.1 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 4-Methoxybenzenethiol (0.23 mL, 5.0 eq.), sodium iodide (288 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.03undec-7ene

[0545] (DBU, 0.17 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2×2 mL), DMF:water 9:1 (2×2 MiL), DMF (2 nL), MeOH (2×2 mL), and DCM (2×2 nL). The resin was dried in vacuo at room 5 temperature.

[0546] Step C: Oxidation of sulfide to sulfoxide.

[0547] N-Hydroxy-2-(4-methoxy-benzenesulfanyl)propionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert-butylhydroperoxide (1.0 nL) and benzenesulfonic acid (50 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 nL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacua at room temperature.

[0548] Step D: Oxidation of sulfide to sulfone.

[0549] N-Hydroxy-2-(4-methoxy-benzenesulfanyl)propionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mnL), and DCM (2×2 mnL). The resin was dried in vacuo at room temperature.

[0550] Step E: Cleavage of N-Hydroxy-2-(4-methoxy-benzenesulfonyl)propionamide from resin.

[0551] The N-Hydroxy-2-(4-methoxy-benzenesulfonyl)propionamide resin prepared in Step D (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 niL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mnL) was added and the mixture concentrated.

[0552] 84% @215 nm; ¹H NMR (DMS0 d-6) 6 10.75 (brs, 1 H), 7.95 (brs, 1 H), 7.71 (dd, 2 H), 7.16 (dd, 2 H), 3.87 (s, 3 H), 3.83 (q, 1 H), 1.26 (d, 3 H).

[0553] The hydroxamic acids of Examples 111-113 are synthesized using appropriate starting materials and following the steps in example 110.

EXAMPLE 111

[0554] N-Hydroxy-2-(4-methoxy-benzenesulfanyl)propionamide. 72% @215 nm

[0555] N-Hydroxy-2-(4-methoxy-benzenesulfnyl)propionamide. 76% @215 nm; ¹H NMR (DMBO d-6) 8 10.90 &10.60 (brs, 1 H), 7.95 (brs, 1 H) 7.61 & 7.52 (dd, 2 H), 7.15 & 7.10 (dd, 2 H), 3.83 & 3.82 (s, 3 H), 3.42 & 3.28 (q 1H), 1.23 & 0.97 (d, 3 H).

EXAMPLE 112

[0556] N-Hydroxy-2-(3-methyl-butane- 1 -sulfanyl)propionamide. 74% @215 nm.

[0557] N-Hydroxy-2-(3-methyl-butane-1-sulfmyl)propionamide. ¹H NMR (DMSO d-6) 8 10.8 (brs 1 H), 7.95 (brs, 1 H), 3.45 & 3.31 (q, 1 H), 2.71 -2.50 (m, 2 H), 1.71-1.46 (m, 3 H), 1.33 & 1.25 (d, 3 H), 0.940.82 (m, 6 H)

EXAMPLE 113

[0558] N-Hydroxy-2-(3-methyl-butane- 1 -sulfonyl)propionaiide. 84% @215 nm.

EXAMPLE 114

[0559] N-hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)butyramide

[0560] Step A: Coupling of 2-bromo-3-methyl-butyric acid to hydroxylamine resin.

[0561] 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)resin'(5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL). 2-Bromo-3-methyl-butyric acid (9.96 g, 10.0 eq.) and DIC (9.04 rnL, 10.5 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DME (3×20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH (2×20 mL), and DCM (2×20 mJL). The resin was dried in vacuo at room temperature.

[0562] Step B: Displacement of bromide with 2-naphthalenethiol.

[0563] The 2-bromo hydroxymate resin prepared in Step A (0.15 g, 1.1 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 2-Naphthalenethiol (138 mg, 5.0 eq.), sodium iodide (129 mg, 5.0 eq.) and 1,8-4azabicyclo(5.4.0]undec-7-ene (DBU, 0.078 iL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2×2 mL), DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mnL). The resin was dried in vacuo at room temperature.

[0564] Step C: Oxidation of sulfide to sulfoxide.

[0565] 2-(2-Naphthalenesulfanyl)N-hydroxypropionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried i vacuo at room temperature.

[0566] Step D: Oxidation of sulfide to sulfone.

[0567] 2-(2-Naphthalenesulfanyl)N-hydroxypropionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCMi (2×2 nL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 rnL). The resin was dried in vacuo at room temperature.

[0568] Step E: Cleavage of N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)butyramide from resin.

[0569] The 2-(2-Naphthalenesulfanyl)N-hydroxypropionamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 rnL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the rixture concentrated. 83% @215 nrn; LCMS (API-electrospray) m/z 276 (M+H)⁺; ¹H NMR (DMSO d-6) 5 10.7 (brs, 1 H), 7.91 (brs, 1 H), 7.91-7.81 (m, 4 H), 7.55-7.45 (m, 3 H), 3.41 (d, 1 H), 2.09-1.97 (m, 1 H), 1.05 (d, 3 H), 0.97 (d, 3 H).

[0570] The hydroxamic acids of Examples 115-118 are synthesized using appropriate starting materials and following the steps in example 114:

EXAMPLE 115

[0571] N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfinyl)butyramide. 67% @215 nm.

EXAMPLE 116

[0572] N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfonyl)butyramide. 97% @215 nm; LCMS (API-electrospray) mlz 308 (M+)⁺.

EXAMPLE 117

[0573] N-Hydroxy-3-methyl-2-phenethylsulfinyl-butyramide. 93% @215 im; LCMS (API-electrospray) m/z 254 (M+H)⁺.

EXAMPLE 118

[0574] N-Hydroxy-3-methyl-2-phenethylsulfonyl-butyramide. 97% @215 nm; LCMS (API-electrospray) m/z 286 (M+H)⁺.

EXAMPLE 119

[0575] (1-Hydroxycarbamoyl-propane-1-sulfanyl)acetic acid methyl ester

[0576] Step A: Coupling of 2-bromobutyric acid to hydroxylamine resin. 4O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%divinylbenzene)resin'(5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL). 2-Bromobutyric acid (3.0 g, 3.0 eq.) HOBt (4.86 g, 6.0 eq.) and DIC (3.75 n2L, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3×20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3×20 mL), MEOH (2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at room temperature.

[0577] Step B:Displacement of bromide with methyl thioglycolate.

[0578] The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.1 meq/g) was placed in a 20 ML scintillation vial and suspended in THF (2 mL). Methyl thioglycolate (286 mg, 5.0 eq.), sodium iodide (404 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.24 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2×2 mL), DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0579] Step C: Oxidation of sulfide to sulfoxide.

[0580] (1-Hydroxycarbamoyl-propane-1-sulfanyl)acetic acid methyl ester resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 1L) and 70% tert-butylhydroperoxide (1.0 1L) benzenesulfonic acid (50 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 nL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0581] Step D: Oxidation of sulfide to sulfone.

[0582] (1-Hydroxycarbamoyl-propane-1-sulfanyl)acetic acid methyl ester resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mLI) and mCPBA (180 mg) was added The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 riL),'DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 rnL). The resin was dried in vacuo at room temperature.

[0583] Step E:Cleavage of (1-Hydroxycarbamoyl-propane-1-sulfanyj)acetic acid methyl ester from resin

[0584] The (1-Hydroxycarbamoyl-propane-1-sulfanyl)acetic acid methyl ester resin prepared in Step B (150 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 IiL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. LCMS (API-electrospray) in/z 228 (M+Na)⁺.

[0585] The hydroxamic acids of Examples 120-124 are synthesized using appropriate starting materials and following the steps in example 119.

EXAMPLE 120

[0586] (1-Hydroxycarbamoyl-propane-1-sulfonyl)acetic acid hydroxyamide. LCMS (API-electrospray) m/z 224 (M+H)⁺.

EXAMPLE 121

[0587] (1-Hydroxycarbamoyl-propane-1-sulfinyl)acetic acid hydroxy amide. 100% @220 nm; LCMS (API-electrospray) m/z 240 (M+H)⁺.

EXAMPLE 122

[0588] (1-Hydroxycarbamoyl-propane-1-sulfanyl)propionic acid hydroxyamide. ¹H NMR (DMSO d-6) δ 10.7 (brs, 1 H), 4.03 (t, 2 H), 2.95 (q, 1 H), 2.75-2.70 (m, 1 H), 2.60-2.54 (m, 1 H), 1.74-1.66 (m, 2 H), 1.58-1.50 (m, 4 H), 1.32 (sextet, 2 H), 0.88 (t, 3 1H), 0.85 (t, 3 H); LCMS (API-electrospray) m/z 264 (M+H)⁺.

EXAMPLE 123

[0589] (1-Hydroxycarbamoyl-propane-1-sulfinyl)propionic acid hydroxyamide. 83% @220 nr; LCMS (API-electrospray) m'z 280 (iM+H)'.

EXAMPLE 124

[0590] (1-Hydroxycarbamoyl-propane-1-sulfonyl)propionic acid hydroxyamide. 100% @220 nm;

EXAMPLE 125

[0591] 2-(4-Hydroxybenzenesulfanyl)N-hydroxy-3-phenyl-propionamide

[0592] Step A. Coupling of 2-bromo-3-phenyl-propionic acid to hydroxylainine resin. 4O-Methylhydroxylamine-phenoxymethylcopoly(styrene-1%Aivinylbenzene)resin'(5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 nl). 2-Bromo-3-phenyl-propionic acid (3.5 g, 3.0 eq.) HOBt (4.4 g, 6.0 eq.) and DIC (3.4 nL, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3×20 mL). A sample of resin was removed and subjected to the Kaiser tesl If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3×20 ruL), MeOH (2×20 mL), and DCM (2×20 ML). The resin was dried i vacuo at room temperature.

[0593] Step B: Displacement of bromide with 4hydroxythiophenol.

[0594] The 2-bromo hydroxymate resin prepared in Step A (0.33 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 4Hydroxythiophenol (250 ma, 5.0 eq.), sodium iodide (297 mg, 5.0 eq.) and 1,8Siazabicyclo[5.4.0]undec-7-ene (DBU, 0.18 mIL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2×2 nL), DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacua at room temperature.

[0595] Step C: Oxidation of sulfide to sulfoxide.

[0596] 2-(4-Hydroxybenzenesulfanyl)N-hydroxy-3-phenyl-propionamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 ml) and 70% tert-butylhydroperoxide (0.73 mL) benzenesulfonic acid (36 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCMi (2×2 mL), DMF (2×2 mL), MeOH (2×2 nL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0597] Step D: Oxidation of sulfide to sulfone.

[0598] 2-(4-Hydroxybenzenesulfanyl)N-hydroxy-3-phenyl-propionamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 nL) and XnCiBA (132 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mnL), DME (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0599] Step E: Cleavage of 2-(4-Hydroxybenzenesulfanyl)N-hydroxy-3-phenyl-propionaride from resin.

[0600] The 2-(4Hydroxybenzenesulfanyl)N-hydroxy-3-phenyl-propionamide resin prepared in Step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a SavanE SpeedVac Plus. Methanol (I mL) was added and the mixture concentrated. 84% @215 n=; ¹H NMR (MSO d-6) 3 10.41 (brs, 1 H), 7.95 (brs (1 H), 7.307.15 (m, 5 H), 7.10 (dd, 2 H), 6.75 (dd, 2 H), 3.53 (q, 1 H), 3.05 (dd, 1 H), 2.79 (dd, 1 H).

[0601] The hydroxamic acids of Examples 126130 are synthesized using appropriate starting materials and following the steps in example 125.

EXAMPLE 126

[0602] 2-(4-Hydroxybenzenesulfinyl)N-hydroxy-3-phenyl-propionamide. 73% @215 nm;

EXAMPLE 127

[0603] 2-(4Hydroxybenzenesulfonyl)N-hydroxy-3-phenyl-propionamide. 77% @215 Hm; ¹H

[0604] NMR (DMSO d-6) 5 10.50 (brs, 1 H), 7.95 (brs, 1 H), 7.68-7.57 (m, 2 H), 7.28-7.17 (m, 3 H), 7.08-7.98 (m, 2 H), 6.95-6.87 (m, 2 H), 3.96 (t, 1 H), 3.02 (d, 2 H).

EXAMPLE 128

[0605] 2-(4Acetylamino-benzenesulfanyl)N-hydroxy-3-phenyl-propionamride. 86% @215 nm; ¹H

[0606] NMR (DMSO d-6) 8 10.50 (brs, 1 H), 10.03 (brs, 1 H), 8.13 (brs, 1 H), 7.56-7.12 (m, 9 H), 3.67 (q, 1 H), 3.08 (dd, 1 H), 2.84 (dd, 1 H), 2.04 (s,3 H)

EXAMPLE 129

[0607] 2-(4Acetylamino-benzenesulfinyl)N-hydroxy-3-phenyl-propionainide. 73% @215 nm.

EXAMPLE 130

[0608] 2(4-Acetylamino-benzenesulfonyl)N-hydroxy-3-phenyl-propionamide. 95% @215 nm;

EXAMPLE 131

[0609] 4HydroxycarbamoylA(4methanesulfanyl-phenylsulfanyl)butyric acid methyl ester

[0610] Step A: Coupling of 2-bromo-5-methyl glutaric acid to hydroxylamine resin. 4O-Methylhydroxylamine-phenoxymethylopoly(styrene-1% djvinylbenzene)resin'(4.5 g, 1.2 meqig) was placed in a peptide synthesis vessel and suspended in DMF (40 niL). S-2-Bromo-5-methyl glutarate (3.87 g, 3.0 eq.) HOBt (4.4 g, 6.0 eq.) and DIC (3.4 mi, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DNF (3×20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling descnbed above was repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at room temperature.

[0611] Step B: Displacement of bromide with 4hydroxythiophenol.

[0612] The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 4-(Methylthio)thiophenol (206 mcg, 5.0 eq.), 20 sodium iodide (197 mg, 5.0 eq.) and 1,8-6azabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DNM (2×2 nL), DMF:water 9:1 (2×2 mL), DMF (2 nmL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0613] Step C: Oxidation of sulfide to sulfoxide.

[0614] 4-Hydroxycarbamoyl(4-methanesulfanyl-phenylsulfanyl)butyric acid methyl ester resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 rnL) benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was fiMtered and washed with DCM (2×2 niL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 rnL). The resin was dried in vacuo at room temperature.

[0615] Step D: Oxidation of sulfide to sulfone.

[0616] 4-Hydroxycarbamoyl4-(4methanesulfanyl-phenylsulfanyl)butyric acid methyl ester resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2×2 mL), DE (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacua at room temperature.

[0617] Step E: Cleavage of 4Hydroxycarbamoyl(4methanesulfanyl-phenylsulfanyl)butyric acid methyl ester from resin.

[0618] The 4-Hydroxycarbamoyl+(4-methanesulfanyl-phenylsulfanyl)butyric acid methyl ester resin prepared in Step B (73 mg, 1.2 meag) was suspended in DCM (1.0 mL) and TFA (1.0 mnL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1InI). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. 77% @215 nm; LCMS (API-clectrospray) mlz 316 (M+H) .

[0619] The hydroxamic acids of Examples 132-139 are synthesized using appropriate starting materials and following the steps in example 131.

EXAMPLE 132

[0620] 4-Hydroxycarbamoyl4-(4-methanesulfinyl-phenylsulfinyl)butyric acid hydroxyamide. 79% @215 nm; LCMS (API-electrospray) mi/z 348 (M+H+.

EXAMPLE 133

[0621] 4-Hydroxycarbamoyl4-(4-methanesulfonyl-phenylsulfonyl)bptyric acid hydroxyamide. 78% @215 nm; LCMS (APIelectrospray) mlz 380 (M+H)⁺.

EXAMPLE 134

[0622] 4-Hydroxycarbamoyl4-(4bromo-benzenesulfanyl)butyric acid hydroxyamide. 93% @215 nm.

EXAMPLE 135

[0623] 4-Hydroxycarbamoyl4-(4-bromo-benzenesulfmnyl)butyric acid hydroxyamide. 80% @215 nm.

EXAMPLE 136

[0624] 4-Hydroxycarbamoyli(4bromo-benzenesulfonyl)butyric acid hydroxyamide. 77% @215 sun.

EXAMPLE 137

[0625] 4Hydroxycarbamoyl4-(2-trifluoromethyl-benzenesulfanyl)butric acid hydroxyamide. 93% @215 nnL

EXAMPLE 138

[0626] 4-Hydroxycarbamoyl4-(2-trifluoromethyl-benzenesulfmyl)butyric acid hydroxyamide. 72% @215 nm.

EXAMPLE 139

[0627] 4-Hydroxycarbamoyl(2-trifluoromethyl-benzenesulfonyl)butyric acid hydroxyamide. 90% @215nm.

EXAMPLE 140

[0628] 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide

[0629] Step A: Coupling of 2-bromo-decanoic acid to hydroxylamine resin.

[0630] 4O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- l.%-divmylbenzene)resin'(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 niL). 2-Bromo-decanoic acid (4.07 g, 3.0 eq.) HOBt (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3×20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DMN (3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried in vacuao at room temperature.

[0631] Step B:Displacement of bromide with 3-methoxy-benzenethiol.

[0632] The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 ML scintillation vial and suspended in THF (2 mL). 3-Methoxy-benzenethiol (185 mg, 5.0 eq.), sodium iodide (197 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 ML, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2×2 mL), DMF:water 9:1 (2×2 mL), DMF (2 rmL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0633] Step C: Oxidation of sulfide to sulfoxide.

[0634] 2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 nL) benrenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 nL), DMF (2×2 mL), MeOH (2×2 L), and DCM (2×2 mL). The resin was dried i vacuo at room temperature.

[0635] Step D: Oxidation of sulfide to sulfone.

[0636] 2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared in Step B (73 mg, 1. meq/g) was suspended in DCM (1.5 mLL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with D (2×2 mL), DNIF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0637] Step E: Cleavage of 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide from resin.

[0638] The 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide resein prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 maL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered Iand the resin washed with DCIM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. 89% @215 nm.

[0639] The hydroxamic acids of Examples 141-145 are synthesized using appropriate starting materials and following the steps in example 140.

EXAMPLE 141.

[0640] 2-(3-Methoxy-benzenesulfinyl)decanoic acid hydroxamide. 96% @215 nm

EXAMPLE 142

[0641] 2-(3-Methoxy-benzenesulfonyl)decanoic acid hydroxamide. 96% @215 noL

EXAMPLE 143

[0642] 2-(4-methanesulfanyl-benzenesulfanyl)decanoic acid hydroxamide. 85% @215 nm; LCMS (API-electrospray) m/z 342 (M+H)⁺.

EXAMPLE 144

[0643] 2-(4-methanesulfinyl-benzenesulfinyl)decanoic acid hydroxamide. 86% @215 imn; LCMS (API-electrospray) m/z 374 (M+H)⁺.

EXAMPLE 145

[0644] 2-(4-methanesulfonyl-benzenesulfonyl)decanoic acid hydroxamide. 92% @215 nm.

EXAMPLE 146

[0645] 3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)propionamride

[0646] Step A: Coupling of 2-bromo-3-benzyloxy propionic acid to hydroxylamine resin. 4-0-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-fdivinylbenzene)resin'(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL). S-2-Bromo-3-benzyloxy-propionic acid (4.2 g, 3.0 eq.) HOBT (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with DMF (3×20 mL). A sample of resin was removed and subjected to the Kaiser test If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH (2×20 mL), and DA (2×20 mxL). The resin was dried in vacuo at room temperature.

[0647] Step B: Displacement of bromide with 4-(methylthio)thiophenol.

[0648] The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 MiL scintillation vial and suspended in THF (2 mL). 4-(Methylthio)thiophenol (206 mg, 5.0 eq.), sodium iodide (197 ma, 5.0 eq.) and 1,8tazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 ML, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction miixture was poured into a polypropylene syringe barrel fitted with a polypropylene fSit, filtered and washed with DMF (2×2 mL), DMF:water 9:1 (2×2 mL), DMF (2 n3L), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0649] Step C: Oxidation of sulfide to sulfoxide.

[0650] 3-Benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)propionamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCIM (2×2 mTL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0651] Step D: Oxidation of sulfide to sulfone.

[0652] 3-Benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)propionamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 ,TL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0653] Step E: Cleavage of 3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl) propionamide from resin.

[0654] The 3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)propionamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 nTL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ′TL) was added and the mixture concentrated. 76% @215 nm; LCMS (API-electrospray) m/z 350 (M+H)⁺.

[0655] The hydroxamic acids of Examples 147-151 are synthesized using appropriate starting materials and following the steps in example 146.

EXAMPLE 147

[0656] 3-Benzyloxy-N-hydroxy-2-(4-methanesUllnyl-benzenesulfmnyl)propionamide. 70% @215 nm; LCMS (API-electrospray) mlz 382 (M+H)⁺.

EXAMPLE 148

[0657] 3-Benzyloxy-N-hydroxy-2-(4-methanesulfonyl-benzenesulfonyl)propionamide. 63% @215 nm; LCMS (API-electrospray) m/z 414 (M+')⁺.

EXAMPLE 149

[0658] 3Benzyloxy-N-hydroxy-2-(2chloro-benzylsulfanyl)propionamide. 90% @215 nm.

EXAMPLE 150

[0659] 3-Benzyloxy-N-hydroxy-2-(2chloro-benzylsulfinyl)propionamde. 70% @215 nin.

EXAMPLE 151

[0660] 3-Benzyloxy-N-hydroxy-2-(2chloro-benzylsulfonyl)prdpionamide. 72% @215 nm.

EXAMPLE 152

[0661] 2-(2 -bromo-benzenesulfanyl)N-hydroxy-3-(3H-imidazolp yl)pro pionam ide

[0662] Step A: Coupling of 2-bromo-3-(3H-imdazol~yl)propionic acid to hydroxylamine resin. 4-0Methylhydroxylamine-phenoxymethylcopoly(styrene-l1%-divinylbenzene)resin'(4-5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mnL). .S-2-Bromo-3-(3H-imidazol~yl)propionic acid (3.55 g, 3.0 eq.) HOBt (4.4 g, 6.0. eq.) and DIC (3.4 nlL, 4.0 eq.) were added& The reaction was shaken on an orbital shaker at room temperature for 2 -16 hours. The reaction was ifiltered and washed with DMF (3×20 mLi). A sample of resin was removed and subjected to the Kaiser test If the test showed the presence of free amine (resin turned blue) the coupling, described above was repeated, otherwise the resin was washed with DCM (3×20 mTL), MeOH (2×20 ′TL), and DCM (2×20 ′TL). The resin was dried in vacuo at room temperature.

[0663] Step B: Displacement of bromide with 2-bromothiophenol.

[0664] The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 ML scintillation vial and suspended in THF (2 mL). 2-Bromothiophenol (249 mg, 5.0 eq.), sodium i6dide (197 mg, 5.0 eq.) and 1,8-diazabicyclo(5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) were added The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2×2 mL), DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 ′TL), and DCM (2×2 ′TL). The resin was dried in vacuo at room temperature.

[0665] Step C: Oxidation of sulfide to sulfoxide.

[0666] 2-(2-Bromobenzenesulfanyl)N-hydroxy-3-(3H-imidazol1yl)propionamide resin prepared is in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mL), DMF (2×2 ′TL), MeOH (2×2 nTL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0667] Step D: Oxidation of sulfide to sulfone.

[0668] 2-(2-Bromo-benzenesulfanyl)N-hydroxy-3-(3H-imidazolyl)propionamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCIM (1.5 rnL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCIM (2×2 ′TL), DMF (2×2 mL), MeOH (2×2 rnL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0669] Step E: Cleavage of 2-(2-bromo-benzenesulfanyl)N-hydroxy-3-(3H-imjdazol4yl) propionamide from resin.

[0670] The 2-(2-bromo-benzenesulfanyl)N-hydroxy-3-(3H-imidazol4-yl)propionamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 ′TL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 ′TL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 nTL) was added and the mixture concentrated. 86% @215 nm.

[0671] The hydroxamic acids of Examples 153-154 are synthesized using appropriate starting materials and following the steps in example 152.

EXAMPLE 153

[0672] 2-(4bromo-benzenesulfnyl)N-hydroxy-3-(3H-imidazolyl)propionamide. 69% @215 nm

EXAMPLE 154

[0673] 2-(4-chloro-benzenesulfonyl)N-hydroxy-3-(3H-imidazol4yl)propionamide.

EXAMPLE 155

[0674] 2-(3-fluorophenylsulfanyl)5-guanidino-pentanoic acid hydroxyamide

[0675] Step A: Coupling of 2-bromo-5-guanidino-pentanic acid to hydroxylamine resin. 40-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)resin'(4.5 g, 1.2 meq/a) was placed in a peptide synthesis vessel and suspended in DMF (40 inL). S-2-Bromo-5-guanidino-pentanic acid (3.85 g, 3.0 eq.) HOBt (4.4 g, 6.0 eq.) and DIC (3.4 niL, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with DMF (3×20 mL). A sample of resin was removed and subjected to the Kaiser test If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated;,otherwise the resin was washed with DCM (3×20 naL), MeOH (2×20 mnL), and DCM (2×20 mL). The resin was dried in vacuo at room temperature.

[0676] Step B: Displacement of bromide with 3-fluorothiophenol.

[0677] The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 rnL scintillation vial and suspended in THF (2 rnL). 3-Fluorothiophenol (169 mu, 5.0 eq.), sodium iodide (197 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2×2 rnL), DhF:water 9:1 (2×2 mL), DMF (2 ni), MeOH (2×2 mnL), and DCM (2×2 rnL). The resin was dried in vacuo at room temperature.

[0678] Step C: Oxidation of sulfide to sulfoxide.

[0679] 2-(3-Fluorophenylsulfanyl)5-guanidino-pentanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 nL) benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 nL). The resin was dried in vacuo at room temperature.

[0680] Step D: Oxidation of sulfide to sulfone.

[0681] 2-(3-Fluorophenylsulfanyl)5-guanidino-pentanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0682] Step E: Cleavage of 2-(3-fluorophenylsulfanyl)5-guanidino-pentanoic acid hydroxyamide from resin.

[0683] The 2-(3-fluorophenylsulfanyl)5-guanidino-pentanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added.

[0684] The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 InL) was added and the mixture concentrated. 93% @215 nm.

[0685] The hydroxamic acids of Examples 156-159 are synthesized using appropriate starting materials and following the steps in example 155:

EXAMPLE 156

[0686] 2-(3-Fluorophenylsulfinyl)5-guanidino-pentanoic acid hydroxyamide. 80% @220 nm; LCMS (API-electrospray) mlz 317 (M+H)⁺.

EXAMPLE 157

[0687] 2-(2-Bromosulfanyl)5-guanidino-pentanoic acid hydroxyamide. 92% @220 nm; ¹H NMR (DMSO d-6) 5 10.90 (brs, 2 H), 10.41 (brs, 1H), 7.95 (brs, 1 H), 7.66-7.14 (m, 5 H), 3.72 (q, 1 H), 3.13 (q, 2 H), 1.90-1.66 (m, 2 H), 1.58-1.43 (2 H).

EXAMPLE 158

[0688] 2-(2-Bromosulfinyl)5-guanidino-pentanoic acid hydroxyamide. 79% @220 nin; LCMS (API-electrospray) m/z 379 (M+H)⁺.

EXAMPLE 159

[0689] 2-(2-Bromosulfonyl)5-guanidino-pentanoic acid hydroxyamide. ¹H NMR (DMSO d-6) 8 8.03-7.45 (m, 5 H), 4.52 (q, 1 H), 3.16 (q, 2 H), 2.07-1.90 (m, 2 H), 1.66-1.59 (2 H).

EXAMPLE 160

[0690] 2-(2,5-dichlorobenzenesulfanyl)octanoic acid hydroxyamide

[0691] Step A: Coupling of 2-bromo-octanoic acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinylbenzene)resin'(10.0 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (80 mL). 2-Bromo-octanoic acid (8.4 g, 3.0 eq.) HOBt (8.8 g, 6.0 eq.) and DIC (7.2 mL, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3×20 rnT). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH (2×20 nL), and DCM (2×20 mL), The resin was dried in vacuo at room temperature.

[0692] Step B: Displacement of bromide with 2,5-dichlorothiophenol.

[0693] The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (6 rnL). 2,5-Dichlorothiophenol (483 mg, 5.0 eq.), sodium iodide (404 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.24 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction rnixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2×2 rnL), DMF:water 9:1 (2×2 mIL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0694] Step C: Oxidation of sulfide to sulfoxide.

[0695] 2-(2,5-Dichlorobenzenesulfanyl)octanoic acid hydroxyamide resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) were added The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried vacuo at room temperature.

[0696] Step D: Oxidation of sulfide to sulfone.

[0697] 2-(2,5-Dichiorobenzenesulfanyl)octanoic acid hydroxyamide resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 mL), DMF (2×2 mnL), MeOH (2×2 mnL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0698] Step E: Cleavage of 2-(2,5-dichlorobenzenesulfanyl)octanoic acid hydroxyamide from resin.

[0699] The 2-(2,5-dichlorobenzenesulfanyl)octanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 rnL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCMI (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 nmL) was added and the mixture concentrated. 92% @215 nm; ¹H NMR (DMSO d-6) 5 10.96 (brs, 1 H), 9.26 (brs, 1 H), 7.93-7.76 (m, 3 H), 4.07 (q, 1 H), 2.041.85 (m, 1 H), 1.78-4.64 (m, 1 H), 1.32-1.09 (m, 8 H), 0.81 (t, 3 H).

[0700] The hydroxamic acids of Examples 161-167 are synthesized using appropriate starting materials and following the steps in example 160.

EXAMPLE 161

[0701] 2-(2,5-Dichlorobenzenesulfonyl)octanoic acid hydroxyamide. 96% @215 nm.

EXAMPLE 162

[0702] 2-(3-Methoxybenzenesulfanyl)octanoic acid hydroxyamide 86% @220 nm; LCMS (API-electrospray) rm/z 298 (M+H)⁺.

EXAMPLE 163

[0703] 2-(3-Methoxybenzenesulfinyl)octanoic acid hydroxyamide 96% @220 am.

EXAMPLE 164

[0704] 2-(3-Methoxybenzenesulfonyl)octanoic acid hydroxyamide 83% @220 nm

EXAMPLE 165

[0705] 2-(3,4Dimethoxybenzenesulfanyl)octanoic acid hydroxyamide 87% @215 nm; LCMS (API-electrospray) m/z 328 (M+H)⁺.

EXAMPLE 166

[0706] 2-(3,4Dimethoxybenzenesulfnyl)octanoic acid hydroxyamide 90% @215 nm.

EXAMPLE 167

[0707] 2-(3,4Dimethoxybenzenesulfony)octanoic acid hydroxyamide 87% @215 nn

[0708] The hydroxamic acid compounds of Examples 168-198 are synthesized using appropriate starting materials and following the steps in example 160. The crude products are dissolved in DMSO:methanol (1:1, 2 mL) and purified by. reverse phase HPLC under the conditions described below:

[0709] Column: ODS-A, 20 mm×50 mm, 5 pm particle size (YMC, Inc. Wilmington, N.C.)

[0710] Solvent Gradient Time Water Acetonitile

[0711] Flow Rate: 15 mL/min. Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 Flow Rate: 15 mL/min.

EXAMPLE 168

[0712] 2-(2-Benzimidazol-2-ylsulfanyl)octanoic acid hydroxyamide 81% @215 nm; LCMS (API-electrospray) m/z 308 (M+H)⁺.

EXAMPLE 169

[0713] 2-(2-Benzooxazol-2-ylsulfanyl)octanoic acid hydroxyamide 72% @215 tim; LCMS (API-electrospray) m/z 309 (M+H)⁺.

EXAMPLE 170

[0714] 2-(2-Benzothiazol-2-ylsulfanyl)octanoic acid hydroxyamide 72% @215 nm; LCMS (API-electrospray) mlz 325 (M+H)⁺.

EXAMPLE 171

[0715] 2-(2-Pyridine-2-sulfanyl)octanoic acid hydroxyamide 76% @215 nrn; LCMS (API-electrospray) m/z 269 (M+H)⁺.

EXAMPLE 172

[0716] 2-(4Phenyl-thiazole-2-sulfanyl)octanoic acid hydroxyahiide 97% @215 nm; LCMS (API-electrospray) rnlz 336 (M+H)'.

EXAMPLE 173

[0717] 2-(2-Pyridin-2-yl-ethylsulfanyl)octanoic acid hydroxyamide 84% @215 Ln; LCMS (API-electrospray) mlz 297 (M+H)⁺.

EXAMPLE 174

[0718] 2-(2-Phenyl-5H-tetrazol-5-ylsulfaayl)octanoic acid hydroxyamide 67% @215 nm; LCMS (API-eIectrospray) mrz 338 (M+H)⁺.

EXAMPLE 175

[0719] 2-(2-Pyrazin-2-yl-ethylsulfanyl)octanoic acid hydroxyamide 98% @215 nn; LCMS (API-electrospray) rn/z 298 (M+H)⁺.

EXAMPLE 176

[0720] 2-(1-Methyl-1H-tetrazol-5-ylsulfanyl)octanoic acid hydroxyamide 66% @215 ni; LCMS (API-electrospray) m/z 274 (M+H)⁺.

EXAMPLE 177

[0721] 2-(2-Benzimidazol-2-ylsulfinyl)octanoic acid hydroxyamide 81% @215 m

EXAMPLE 178

[0722] 2-(2-Pyridine-2-suflnyl)octanoic acid hydroxyamide 76% @215 rnm;.

EXAMPLE 179

[0723] 2-(4Phenyl-thiazole-2-sulfinyl)octanoic acid hydroxyamide 78% @215 rnm.

EXAMPLE 180

[0724] 2-(2-Pyrazin-2-yl-ethylsulfinyl)octanoic acid hydroxyamide 96% @215 nmn; LCMS (API-electrospray) mlz 314 (M+H).

EXAMPLE 181

[0725] 2-(3-Oxy-1H-benzmidazole-2-sulfonyl)octanoic acid hydroxyamide 63% @215 nmn; LCMS (API-electrospray) rnlz 356 (M+H)'. r

EXAMPLE 182

[0726] 2-(4-Phenyl-thiazole-2-sulfonyl)octanoic acid hydroxyamide 70% @215 nrm; LCMS (API-electrospray) m/z 383 (M+H)⁺.

EXAMPLE 183

[0727] 2-[2-(1-Oxy-pyridin-2-yl)ethanesulfonyl]-octanoic acid hydroxyamide 77% @215 nm; LCMS (API-electrospray) m/z 345 (M+H) +.

EXAMPLE 184

[0728] 3-(1-Hydroxycarbamoyl-heptylsulfanyl)benzoic acid hydroxyamide. 100% @220 imm; LCMS (API-electrospray) m/z 312 (M+H)⁺.

EXAMPLE 185

[0729] 3-[4-(1-Hydroxycarbamoyl-heptylsulfanyl)phenyl]-propionic acid hydroxyamide. 90% @220 nm; LCMS (API-electrospray) m/z 340 (M+Ii).

EXAMPLE 186

[0730] 2-(Thiazol-2-ylsulfanyl)octanoic acid hydroxyamide. 75% @215 nm; LCMS (API-electrospray) m/z 275 (M+H)⁺.

EXAMPLE 187

[0731] 2′,72,5-Dioxo-imidazolidinmylmethylsulfanyl)octanoic acid hydroxyamide. 98% @215 nm; CMS (API-electrospray) m/z 304 (M+H)⁺.

EXAMPLE 188

[0732] 3-(1-Hydroxycarbamoyl-heptylsulfmyl)benzoicacid hydroxyamide. 84% @220 nm; LCMS

EXAMPLE 189

[0733] 3-[4-(1-Hydroxycarbamoyl-heptylsuilfinyl)phenyl]-propionic acid hydroxyaminude. 78% @220 nm; LCMS (API-electrospray) mlz 356 (M+H)⁺.

EXAMPLE 190

[0734] 2-(Quinoline-8-sulfinyl)octanoic acid hydroxyamide. 87% @220 nm; LCMS (API-electrospray) mlz 335 (M+H)⁺.

EXAMPLE 191

[0735] 2-(Naphthalen-2-ylcarbamoylmedtanesuIfinyl)octanoic acid hydroxyamide. 83% @220 n; LCMS (APIelectrospray) m/z 391 (M+H).

EXAMPLE 192

[0736] 3-(1-Hydroxycarbamoyl-heptylsulfonyl)benzoic acid hydroxyamide. 72% @215 rm.

EXAMPLE 193

[0737] 3-[4-(1-Hydroxycarbamoyl-heptylsulfonyl)phenyl]-propionic acid hydroxyamide. 67% @215nm.

EXAMPLE 194

[0738] 2-(1H-Imidazole-2-sulfonyl)octanoic acid hydroxyamide. 95% @215 nm; LCMS (API-electrospray) mlz 290 (M+H)⁺.

EXAMPLE 195

[0739] 2-(Thiazol-2-ylsulfonyl)octanoic acid hydroxyamide. 91% @215 nm; LCMS (API-electrospray) mnlz 307 (M+H)f.

EXAMPLE 196

[0740] 2-(Quinoline-8-sulfonyl)octanoic acid hydroxyamide. 94% @220 nm; LCNIS (API-electrospray) mnz 351 (M+H)⁺.

EXAMPLE 197

[0741] 2-(Naphthalen-2-ylcarbamoylmethanesulfonyl)octanoic acid hydroxyamide. 79% @220 nim; LCMS (API-electrospray) m/z 407 (M+H)⁺.

EXAMPLE 198

[0742] 2-(2,5-Dioxoimidazolidin4ylmethylsulfonyl)octanoic acid hydroxyamide. 97% C 215 nm.

EXAMPLE 199

[0743] Step A: Displacement of bromide with 4fluorothiophenol.

[0744] The 2-bromo hydroxymate resin prepared in Example 160, Step A (9.4 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in TBF (50 rnL). 4Fluorothiophenol (6.6 g, 5.0 eq.), sodium iodide (7.7 g, 5.0 eq.) and 1,8Aiazabicyclo[5.4.0]undec-7-ene (BU, 4.6 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours, then filtered and washed with DMF (2×30 mL), DMF:water 9:1 (2×30 mL), DMF (30 mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at room temperature.

[0745] Step B: Couplig of 2-(4fluorobenzenesulfanyl)octanoic acid hydroxyamiide resin with benzyl alcohol.

[0746] 2-(4Fluorobenzenesulfanyl)octanoic acid hydroxyamide resin prepared in Step A (330 mg, 1.1 meq/g) was suspended in DMF (2.0 mL) and benzyl alcohol (731 mg, 15 eq.) and sodium hydride (237 mg, 15 eq.) were added. The reaction was heated to 80° C. for 15 hours while shaking on an orbital shaker. After cooling to room temperature the mixture was filtered and washed with DMF (2×2 mL), DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM (2 x 2 nI). The resin was dried in vacuo at room temperature.

[0747] Step C: Oxidation of sulfide to sulfoxide.

[0748] 2-(2 Benzyloxy-phenylsulfanyl)octanoic acid hydroxyamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 mL) and 70% tert-butylhydroperoxide (0.73 nL) benzenesulfonic acid (36 mg) were added. The reactions mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 nL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 m ).The resin was dried in vacuo at room temperature.

[0749] Step D: Oxidation of sulfide to sulfone.

[0750] 2-(4Benzyloxy-phenylsulfanyl)octanoic acid hydroxyamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 mL) and mCPBA (132 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×2 rnL), DMF (2×2 mL), MeOH (2×2 rnL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0751] Step E: Cleavage of 2-(4benzyloxy-benzenesulfanyl)octanoic acid hydroxyamide from resin.

[0752] The 2-(4benzyloxy-phenylsulfanyl)octanoic acid hydroxyamide resin prepared in Step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 mL ) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was fitered and the resi washed with DCM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ′[L) was added and the mixure concentrated. The crude product was dissolved in DMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under the conditions described below:

[0753] Columni: ODS-A, 20mn×50 mm, 5 Im particle size (YMC, Inc. Wilmington, N.C.)

[0754] Solvent Gradient Time Water Acetonitrile Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 Flow Rate: 15 mL/min.

[0755] Flow Rate: 15 mljmin.

[0756] 2-(4Benzyloxy-phenylsulfanyl)octanoic acid hydroxyanide 100% @215 nm; LCMS (API-electrospray) m/z 374 (M+H)⁺.

[0757] The hydroxamic acid compounds of Examples 200-220 are synthesized using appropriate starting materials and following the steps in example 199:

EXAMPLE 200

[0758] 2-(4Butoxy-berizenesulfanyl)octanoic acid hydroxyamide 100% @215 n'1; LCMIS (API-electrospray) mlz 374 (M+H)⁺.

EXAMPLE 201

[0759] 2-(>(2-Piperazine-1-yl-ethoxy)benzenesulfanyl]-octanoic acid hydroxyamide 98% @215 nm; LCMS (API-electrospray) m/z 340 (M+H)⁺.

EXAMPLE 202

[0760] 2-[4-(5-Hydroxy-pentyloxy)phenylsulfanyl]-octanoic acid hydroxyamide 65% @215 nm.; LCMS (API-electrospray) n~z 370 (M+H)⁺.

EXAMPLE 203

[0761] 2-~[(3-Pyridin-2-yl-propoxy)benzenesulfanyl]-octanoic acid hydroxyamide 95% @215 rnm; LCMS (API-electrospray) m/z 403 (M+H)⁺.

EXAMPLE 204

[0762] 2-(4Benzyloxy-phenylsulfinyl)octanoic acid hydroxyamide 100% @215 nm

EXAMPLE 205

[0763] 2-(4Butoxy-benzenesulfinyl)octanoic acid hydroxyamide 98% @215 nm.

EXAMPLE 206

[0764] 2-[4-(2-Piperazine-1-yl-ethoxy)benzenesulfinyl]-octanoic acid hydroxyamide 98% @215 nm.

EXAMPLE 207

[0765] 2-[4-(3-Pyridin-2-yl-propoxy)benzenesulfinyl]-octanoic acid hydroxyamide 99% @215 rmn.

EXAMPLE 208

[0766] 2-(4Benzyloxy-phenylsulfonyl)octanoic acid hydroxyamnide 100% @215 nm

EXAMPLE 209

[0767] 2-(4-Butoxy-benzenesulfonyl)octanoic acid hydroxyamide,100% 9 215 nm.

EXAMPLE 210

[0768] 2-[4-(2-Piperazine-1-yl-ethoxy)-benzenesulfonyl]-octanoic acid hydroxyamide 97% @215 nm.

EXAMPLE 211

[0769] 2-[4-(3-Pyridin-2-yl-propoxy)benzenesulfonyl1]octanoic acid hydroxyamide 100% @215 nm.

EXAMPLE 212

[0770] 2-[4-(1-Methyl-pyrrolidin-3-yloxy)benzenesulfanyl]-octanoic acid hydroxyamide 91% @215 nm; LCMS (APIlectrospray) m/z 367 (M+H)⁺.

EXAMPLE 213

[0771] 2-[4-(1-Ethyl-propoxy)benzenesulfanyl]-octanoic acid hydroxyamide 100% @215 n;

[0772] LCMS (API-electrospray) m/z 354 (M+H)⁺.

EXAMPLE 214

[0773] 2-[4-(Tetrahydropyraniyloxy)benzenesulfanyl]-octanoic acid hydroxyamide 97% @215 nm; LCMS (API-electrospray) mlz 368 (M+H)⁺.

EXAMPLE 215

[0774] 2-[4-(1-Methyl-pyrrolidin-3-yloxy)benzenesulfmyl]-octanoic acid hydroxyamide 96% @215 nm.

EXAMPLE 216

[0775] 2-[s(1-Ethyl-propoxy)benzenesulfmnyl]-octanoic acid hydroxyamide 97% @215 nm.

EXAMPLE 217

[0776] 2->(Tetrahydro-pyran4-yloxy)benzenesulfinyl]octanoic acid hydroxyamide 97% @215 nm.

EXAMPLE 218

[0777] 2-[4-(1 -Methyl-pyrrolidin-3-yloxy)-benzenesulfonyl]octanoic acid hydroxyamide 96% @215 nm.

EXAMPLE 219

[0778] 2-[4-(1-Ethyl-propoxy)benzenesulfonyl]octanoic acid hydroxyamide 100% @215 nm.

EXAMPLE 220

[0779] 2-[4-(Teaydro-pyran4yloxy)benzenesulfonyl]-octanoic acid hydroxyamide 100% @215

EXAMPLE 221

[0780] Step A: Displacement of bromide with 4bromothiophenol.

[0781] The 2-bromo-octanoic acid hydroxymate resin prepared in Example 160, Step A (5.0 g, 1.1 me/g) was placed in a peptide synthesis vessel and suspended in THF (60 m'). 4 Bromothiophenol (5.2 g, 5.0 eq.), sodium iodide (4.1 g, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.5 rmi, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours, then filtered and washed with DMF (2×30 nL), DMF:water 9:1 (2×30 inL), DMF (30 rnL), MeOH (2×30 ′TL), and DCM (2×30 raL). The resin was dried in vacuo at room temperature.

[0782] Step B: Oxidation of sulfide to sulfoxide.

[0783] 2-(4Bromobenzenesulfanyl)octanoic acid hydroxyamide resin prepared in Step A (4.4 g, 1.1 meq/g) was suspended in DCM (60 mL) and 70% tert-butylhydroperoxide (30 mnL) benzenesulfonic acid (1.5 g) were added. The reaction nixnture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×30 mL), DMF (2×30 mL), lvleOH (2×30 mL), and DCIM (2×30 mL). The resin was dried in vacuo at room temperature.

[0784] Step C: Oxidation of sulfide to sulfone.

[0785] 2-(4Bromobenzenesulfanyl)octanoic acid hydroxyamide resin prepared in Step B (4.4 g, 1.1 meq/g) was suspended in DCM (60 ml) and mCPBA (5.2 g) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×30 mL), DMF (2×30 mL), MeOH (2×30 m'L), and DCM (2×30 mL). The resin was dried in vacuo at room temperature.

[0786] Step D: Coupling of 2-(4bromobenzenesulfinyl)octanoic acid hydroxyamide resin with 4 chlorobenzeneboronic acid.

[0787] 2-(4Bromobenzenesulfmyl)octanoic acid hydroxyamide resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DMB (2.0 mL) and nitrogen gas bubbled through the suspension for 1-2 minutes. 4Chlorobenzeneboronic acid (51.6 mg, 2 eq.), tetrakis(triphenylphosphine) palladium(0) (19.07 mg, 0.1 eq.) and sodium carbonate (2 M solution, 0.825 mL, 10 eq.) were added. The reaction was heated to 80° C. for 8 hours while shaking on an orbital shaker.

[0788] After cooling to room temperature the mixture was filtered and washed with DME (2×2 mL), DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried i vacuo at room temperature.

[0789] Step E: Cleavage of 2-(4′-chloro-biphenylsuffinyl)octanoic acid hydroxyamide from resin.

[0790] The 2-(4′hlorobiphenyl4sulfinyl) octanoic acid hydroxyamide resin prepared in Step D (150 mg, 1.1 meq/g) was suspended in DCM (1.0 mL) and TPA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mnL) was added and the mixture concentrated. The crude product was dissolved in DMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under the conditions descnbed below:

[0791] Column: ODS-A, 20mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington, N.C.)

[0792] Solvent Gradient Time Water Acetonitrile Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 Flow Rate: 15 mL/min.

[0793] Flow Rate: 15 mL/min.

[0794] 2-(4′-Chloro-biphenyltsulfinyl)octanoic acid hydroxyamide 96% @215 nm; LCMS (API-electrospray) m/z 394 (M+H)⁺.

[0795] The hydroxamic acid compounds of Exmples 222-224 are synthesized using appropriate starting materials and following the steps in example 221:

EXAMPLE 222

[0796] 2-[4-(5-Chloro-thiophen-2-yl)benzenesulfmyl]-octanoic acid hydroxyamide 100% @215 nrn LCMS (API-electrospray) m/z 400 (M+H)⁺.

EXAMPLE 223

[0797] 2-(4′-Chloro-bipheny14sulfonyl)octanoic acid hydroxyamide 94% @215 nm; LCMS (API-electrospray) m/z 410 (M+H)⁺.

EXAMPLE 224

[0798] 2-[4-(5-Chloro-thiophen-2-yl)benzenesulfonyl]-octanoic acid hydroxyamide 85% @215 nm;

[0799] LCMS (API-electrospray) m/z 416 (M+H)⁺.

EXAMPLE 225

[0800] Step A: Coupling of 2-(4bromobenzenesulfanyl)octanoic acid hydroxyamide resin with N-(3-aminopropyl)morpholine.

[0801] 2-(4-Bromobenzenesulfanyl)octanoic acid hydroxyamide resin prepared in Example 199, Step A (100 mg, 1. Imeq/g) was suspended in dioxane (2.0 mL) and nitrogen gas bubbled through the suspension for 1-2 minutes. N-(3-Arrinopropyl)morpholine (346 mg, 20 eq.), tris(dibenzylideneacetone) dipalladium(0) (22 mg, 0.2 eq.), (S)(—)2,2′-bis(diphenylphosphino)l,l'-binaphthyl((S)BINAP, 60 mg, 0.8 eq.) and sodium tert-is butoxide (207 mg, 18 eq.) were added. The reaction was heated to 80° C. for 8 hours while shaking on an orbital shaker. After cooling to room temperature the mixture was filtered and washed with DMF (2×2 mL), DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature.

[0802] Step B: Cleavage of 2-[4-(3-morpholin~yl-propylamino)phenylsulfanyl]-octanoic acid hydroxyamide from resin.

[0803] The 2-[4-(3-morpholinfiyl-propylamino)phenylsulfanyl]-octanoic acid hydroxyamide resin prepared in Step A ( 100 mg, 1.1 meq/g) was suspended in DCiM (1.0 mL) and TFA (1.0 rnL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mnL) was added and the mixture concentrated. The crude product was dissolved in DMSO:methanol (1:1, 2 nlL) and purified by reverse phase HPLC under the conditions described below:/

[0804] Column: ODS-A, 20mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington, N.C.)

[0805] Solvent Gradient Time Water Acetonitrile Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 Flow Rate: 15 mL/min.

[0806] Flow Rate: 15 mL/min.

[0807] 2-[4-(3-morpholin4yl-propylamino)phenylsulfanyl]-octanoic acid hydroxyamide 88% @215 n; LCMS (API-electrospray) mlz 410 (M+H)⁺.

[0808] The hydroxamic acid compounds of Examples 226-231 are synthesized using appropriate startng materials and following the steps in this example:

EXAMPLE 226

[0809] 2-[4-(BiphenylylamInmo)phenylsulfanyl]loctanoic acid hydroxyamide 95% @215 nm; LCMS (API-electrospray) mlz 435 (M+H)⁺.

EXAMPLE 227

[0810] 2-[4-(Pyridin4ylamino)phenylsulfanyl]-octanoic acid hydroxyamide 97% @215 nm; LCMS (API-ectrospray) mlz 360 (M+H)⁺.

EXAMPLE 228

[0811] 2-(4Cyclopentylamino-phenylsulfanyl)ctanoic acid hydroxyamide 77% @215 nr; LCMS (API-electrospray) m/z 351 (M+H)⁺.

EXAMPLE 229

[0812] 2-(4-Methylamino-phenylsulfanyl)octanoic acid hydroxyamide 99% @215 nm; LCMS (API-electrospray) m/z 297 (M+H)⁺.

EXAMPLE 230

[0813] 2-(4Piperidin-1-yl-phenylsulfanyl)ctanoic acid hydroxyamide 72% @215 nm; LCMS (API-electrospray) m/z 351 (M+H)⁺.

EXAMPLE 231

[0814] 2-(4Piperazin-1-yl-phenylsulfanyl)octanoic acid hydroxyamide 74% @215 mn; LCMS (API-electrospray) m/z 352 (M+H)⁺.

EXAMPLE 232

[0815] Step A: Displacement of bromide with 4hydroxythiophenol.

[0816] The 2-bromo-octanoic acid hydroxymate resin prepared in Example 160, Step A (15.0 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in THF (120 mL). 4 Hydroxythiophenol (11.3 g, 5.0 eq.), sodium iodide (13.5 g, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 8.1 mrL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours, then filtered and washed with DMF (2×60 mL), DMf:water 9:1 (2×60 mL), DMF (60 n2L), MeOH (2×60 inL), and DCM (2×60 mxL). The resin was dried in vacuo at room temperature.

[0817] Step B: Coupling of 2(4hydroxybenzenesulfanyl)otanoic acid hydroxyamide resin with benzene sulfonyl chloride.

[0818] 2-(4-Hydroxybenzenesulfanyl)octanoic acid hydroxyamide resin prepared in Step A (240 mg, 1.2 meq/g) was suspended in DCM (3.0 ′x). Benzene sulfonyl chloride (225 mg, 5 eq.), and triethylamine (0.06 mL, 2 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 8 hours, then filtered and washed with DME (2×2 mi), DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

[0819] Step C: Oxidation of sulfide to sulfoxide.

[0820] Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)phenyl ester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 ′xL),and 70% tert-butylhydroperoxide (1 mL) benzenesulfonic acid (23 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×3 mL), DMF (2×3 mL), MeOH (2×3 mL), and DCIM (2×3 mL). The resin was dried in vacuo at room temperature.

[0821] Step D: Oxidation of sulfide to sulfone.

[0822] Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)phenyl ester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 mL) and mCPBA (84 mg) was added. The reaction nixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2×3 mxL), DMF (2×3 mL), MeOH (2×3 mL), and DCM (2×3 ′L). The resin was dried in vacuo at room temperature.

[0823] Step E: Cleavage of benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)phenyl ester resin.

[0824] The benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)phenyl ester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TEA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2×1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (I mL) was added and the mixture concentrated The crude product was dissolved in DMSO methanol (1:1, 2 mL) and purified by reverse phase HPLC under the conditions descnbed below:

[0825] Column: ODS-A, 20mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington, N.C.)

[0826] Solvent Gradient Time Water Acetonitrile Solvent Gradient Time Water Acetonitrile 0.0 95 5 25 min.  5 95 Flow Rate: 15 mL/min.

[0827] Flow Rate: 15 mL/min.

[0828] Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)phenyl ester 91% @215 nm;

[0829] LCMS (API-electrospray) m/z 424 (M+H)⁺.

[0830] The hydroxamic acid compounds of Examples 233-240 are synthesized using appropnate starting materials and following the steps in example 232:

EXAMPLE 233

[0831] 2,5-Dichloro-thiophene-3-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)hydroxyarride 98% @215 nm; LCMS (API-electrospray) m/z 498 (M+H)⁺..r.

EXAMPLE 234

[0832] Ethanesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)hydroxyamide. 72% @215 nm; LCMS (API-electrospray) m/z 376 (M+H)⁺.

EXAMPLE 235

[0833] 5-Chloro-1,3-dimethyl-1H-pyrazolefsulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfinyl) hydroxyamide 99% @215 nm; LCMS (API-electrospray) rnz 492 (M+H)⁺.

EXAMPLE 236

[0834] 2,5-Dichlorothiophene-3-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfnyt)hydroxyamide 96% @215 nm; LCMS (APIeectrospray) mlz 514 (M+H)⁺.

EXAMPLE 237

[0835] 5-Pyridin-2-yl-thiophene-2-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfinyl)hydroxy amaide 96% @215 nm; LCMS (API-electrospray) mlz 523 (M+H)⁺.

EXAMPLE 238

[0836] 2-Nitrbenzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfonyl)hydroxyamide 97% @215 nm; LCMS (API-electrospray) m/z 501 (M+H)⁺.

EXAMPLE 239

[0837] 3-Bromo-2-chloro-thiophene-2-sulfonic acid 4-( 1-hydroxycarbamoyl-heptylsulfonyl) hydroxyamide 97% @215 nm; LCMS (API-electrospray) rmz 576 (M+H)⁺.

EXAMPLE 240

[0838] Benzo[ 1 ,2,5]thiadiazole4sulfonic acid 4-(1 -hydroxycarbamoyl-heptylsulfonyl) hydroxyamnide 83% @215 nm; LCMS (API-electrospray) m/z'514 (M+H)⁺.

EXAMPLE 241

[0839] 1-Benzyl-4-(4benzyloxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 rmmol) and anhydrous K2C₀₃ (10 gm, excess) in dry acetone (100 ml), α-bromo ethyl acetate (3.3 gm, 20 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H20 and 0.5 N NaOH solution. The organic layer was further washed well with water, dried over MgSO₄, filtered and concentrated. (4-methoxy-phenylsulfanyl)acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%); MS; 227 (M+H)⁺

[0840] To stirred solution of (4-methoxy-phenylsulfanyl)acetic acid ethyl ester (4.4 g, 20 inmol), anhydrous K₂CO₃ (10 gm excess) in dry acetone (1000 ml) benzyl bromide (3.5 g, 20 mnmol) was added and refluxed for 4 hrs. At the end, reaction mixture was fltered , concentrated and the residue was extracted with chloroform. It was washed well with water, dried and concentrated. The crude product obtained was converted to (4-benzyloxy-phenylsulfonyl) acetic acid ethyl ester by oxidaizing with m-chloro perbenzoic acid as described in the example 83. Low melting solid. Yield: 6.6 g, 97%; MS: 335 (M+l)

[0841] To a stirred solution of bis-(2-chloro-ethyl)benzyl amine hydrochloride (6.6 g, 24.7 remol), 18-Crown-6 (500 mg), and anhydrous K2CO₃ (30 gm, excess) in dry acetone (250 ml), (4 benzyloxy-phenylsulfonyl)acetic acid ethyl ester (8.01 gm, 24 mmol) was added in a round bottom flask and the reaction mLxture was heated at reflux for 16 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H₂O . The organic layer was further washed well with water, dried over MgSO₄, filtered and concentrated. The dark brown reaction mixture was purified by silica gel coumn chromatography by eluting it with 30% ethylacetate: hexane and the product 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine~carboxylic acid ethyl ester was isolated as Brown oil. Yield: 6.5 g, 55%; MS: 494 (M+H)

[0842] 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.1 mmol) was dissolved in MeOHF (1:1, 200 ml) and stirred at room temperature for 72 hrs. At the end reaction mixture was concentrated and the product *as nuetralised with con. HCl by dissolving it in water (200 ml). After the nuetralization reaction mixture was concentrated to dryness. Ice cold water (100 ml) was added to the solid and filtered. The product (4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4 carboxylic acid was dried at 50 C and taken to next step with out any purification. Colorless solid. MP: 66-68; Yield: 4.3 g, 91%;MS: 466 (M+H)

[0843] Starting from 4-(4Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine~carboxylic acid (4.65 g, 10.0 mmol) and following the procedure outlined in example 83, 1.1 g of 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a colurless solid. Yield 21%; mp 89 ° C.; MS: 481.1 1H NMR (300 MHz, DMSO-d6): 5 2.27 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H), 9.37 (s,1H), 10.53 (s,1H), 11.18 (s,1H).

EXAMPLE 242 4-(4Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-piperidin e-carboxylic acid hydroxyamide

[0844] from 2-[(2-Hydroxy-ethyl) f4-(2-piperidin-1-yl-ethoxy)benzyl]-amine was prepared according to the general method outlined in example 83 starting from diethanolamine (15.0 g, 150). and 4-(2-piperidin-1-yl-ethoxy)benzyl chloride (5.9 g, 20 mmol). Yield 5.5 g, (85%); Brown semi-solid; MS: 323 (M+H)⁺

[0845] Bis-(2-chloro-ethyl)[$(2-piperidin-1-yl-ethoxy)benzyl]-amine was prepared according to the general method outlined in example 83 starting from 2-[(2-Hydroxy-ethyl) [4-(2-piperidin-1-yl-ethoxy)benzyl]-amine (3.22 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H)⁺

[0846] 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-piperidine~carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (6.0 g, 20 imnol) and Bis-(2-chloro-ethyl)[4-(2-piperidin-1-yl-ethoxy)benzyl]-amine,(8.6 ′g, 20 mmol). Yield 8.0 g (68%); brown oil; MS: 587.7 (M+H)⁺*

[0847] 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy) benzyl]-piperidineA carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-piperidinefcarboxylic acid ethyl ester (5.8 g, 10 mn=ol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98 ° C.; MS: 559.6 (M+H)⁺

[0848] Starting from 4-(4butoxy-benzenesulfonyl)-1-[>(2-piperidin-1-yl-ethoxy)benzyl]-piperidine-4-carboxylic acid (5.5 g, 10 mmol) and following the procedure outlined in example 83, 2.4 g of 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-piperidine-4-carboxylic acid hydroxy amidewas isolated as a pale yellow solid. Yield 41%; mp 155 ° C. (HCl); MS: 574 (M+H)'; ¹H NMR (300 M~I, DMSO-dd: 8 0.9 (t, 3H), 1.1-1.8 (m, 6H), 1.9 (m, 4H), 2.3 (m, 4H), 2.8 (m, 6H), 3.2-3.6 (m, 8H), 4.2 (m, 2H), 6.9 - 7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).

EXAMPLE 243 4(4-Butoxy-benzenesulfonyl) 1-[3-(2-morpholinyl- 1-yl-ethoxy)benzyl]-piperidine-4 carboxylic acid hydroxyamide

[0849] Bis-(2-hydroxyethyl)[3-(2-morpholin-1-yl-ethoxy)benzyl]-amine was prepared according to the general method outlined in example 83 starting from diethanolamine (15.0 g, 150). and 3-(2-morpholin-1-yl-ethoxy)benzyl chloride (5.9 g, 20 mmol). Yield 6.2 g, (95%); Brown semi-solid; MS: 325 (M+H)'

[0850] Bis-(2-chloro-ethyl)[3t2-morpholin-1-yl-ethoxy)benz yl]-anine was prepared according to the general method outlined in example 83 starting from Bis-(2-Hydroxy-ethylI) [3-(2-morpholin-1-yl-ethoxy)benzyl]-amine (3.24 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 363.1 (M+H)'

[0851] 4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)benzyl]-piperidin e-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from from 4butoxy-benzenesulfonyl) acetic acid ethyl ester (6.0 g, 20 mmol) and Bis-(2-chloro-ethyl)[3-(2-morpholin-1-ylethoVy)benzyl]-amine (8.6 g, 20 mmol). Yield 8.5 g (72%); brown oil; MS: 589.7 (M+H)⁺

[0852] 4-(4-Butoxy-benzenesulfonyl) 1 -[3-(2-morpholin- 1-yl-ethoxy)benzyl]-piperidineX carboxylic acid was prepared starting from 4-(4Butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 rmnol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (85%); Spongy brown solid; MS: 561.6 (M+H)⁺Starting from 4-(4butoxy-benzenesuIfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)benzyl]-piperidine-carboxylic acid (5.6 g, 10 mmol) and following the procedure outlined in example 83, 4.02 g of 4-(4butoxy-benzenesulfonyl) 1 -[3-(2-morpholin-1 -yl-ethoxy)benzyl]-piperidine-carboxylic acid hydroxy amidewas isolated as a pale yellow solid. Yield 62%; mp 123 ° C. (HCl); MS: 576 (M+H)⁺; ¹H NMR (300 MHz, DMS O-do: 5 0.9 (t, 3H), 1.4 (m, 2H), 1.8 (t, 2H), 2.34.7 (m, 24H), 7.0- 7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).

EXAMPLE 244 1-Methyl~(4-butoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

[0853] 1-Methyl-4-(4-butoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from Butoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 10 mmol) and methyl-bis-(2chloro-ethyl)anine (2.2g, 11.6 mmol). Yield 4.0 g, (98%); low melting brown solid; MS: 384 (M+H)⁺1-Methyl-4-(4-butoxy-benzenesulfonyl)piperidine-4-carboxylic acid was prepared stardtng from 1-methyl-4-(4butoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (7.6 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). The resulting reaction 1A mixture was worked up outlined in example 83. Yield 6.0 g (84%); white solid; mp 195 ° C.; MS: 356.4 (M+H)⁺

[0854] Starting from 1-methyl-4-(4butoxy-benzenesulfonyl)piperidine~carboxylic acid (4.0 g, 11.2 mmol) and following the procedure outlined in example 83, 3.9 g of 1-methyl-4-(4 butoxy-benzenesulfonyl)piperidine~carboxylic acid hydroxyaride was isolated as a yellow powder. Yield 85%; mp 118 ° C.; MS: 371 (M+H); ¹H NMR (300 MHz, DMSO-d₆): 5 0.9 (t, 3H), 1.45 (q, 2H), 1.8 (q, 2H), 2.1 (s, 3H), 2.3 (d, J 11.4 Hz, 2H), 2.5-3.7 (m, 8H), 4.1 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H)

EXAMPLE 245

[0855] 1-Ethyl-4-(4butoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide 1 -Ethyl-4-(4butoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 10 mmol) and ethyl-bis-(2chloro-ethyl)amine (2.2g, 10.6 mmol). Yield 3.5 g, (88%); low melting brown solid; MS: 398 (M+H)⁺1-Ethyl-4-(4butoxy-benzenesulfonyl)piperidine-4-carboxylic acid was prepared starting from 1-ethyl-4-(4butoxy-benzenesulfonyl)piperidine~carboxylic acid ethyl ester (7.94 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 rrl). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.5 g (88%); white solid; mp 162 OC; MS: 370 (M+H)⁺

[0856] Starting from 1-ethyl-4-(4-butoxy-benzenesulfonyl)piperidine-4 arboxylic acid (3.7 g, 10 mmol) and following the procedure outlined in example 83, 3.2 g of 1-ethyl-4-(4-butoxy-benzenesulfonyl)piperidinefarboxylic acid hydroxyamide was isolated as a yellow powder. Yield 76%; mp 98 ° C.; MS: 385 (M+H)⁺; ¹H NMR (300 MIz, DMSO-dd: 5 0.9 (t, 3H), 1.2 (t, 3H), 1.46 (q, 2H), 1.9 (q, 2H), 2.3 (d, J=11.4 Hz, 2H), 2.5-3.6 (m, 1OH), 4.1 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H)

EXAMPLE 246 1-n-Butyl (4-butoxy-benzenesulfonyl )piperidine-4-carboxylic acid hydroxyamide

[0857] 1-n-Butyl4-(4butoxy-benzenesulfonyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from SButoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 10 mmol) and n-butyl-bis-(2-chloro-ethyl)amine (2.0 g, 10.1 mmol). Yield 3.8 a, (89%); low melting brown solid; MS: 426 (M+H)⁺1-n-Butyl4-(4-butoxy-benzenesulfonyl)piperidine-4-carboxylic acid was prepared starting from 1-n-Butyl4-(4butoxy-benzenesulfonyl)piperidine-4,carboxylic acid ethyl ester (8.5 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 rnl). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.5 ga(88%); white solid; mp 182 ° C.; MS: 398 (M+H)⁺

[0858] Starting from 1-n-butyl(4butoxy-benzenesulfonyl)piperidine~carboxylic acid (3.9 g, 10 mmol) and following the procedure outlined in example 83, 1.8 g of 1-n-butyl-4-(4-butoxy-benzenesulfonyl)piperidine-4arboxylic acid hydroxyamide was isolated as a yellow powder. Yield 40%; mp 121 ° C.; MS: 413 (M+H)⁺; ¹H NMIR (300 MHz, DMSO-d₆): 6 0.9-1.0 (m, 6H), 1.2-1.8 (m, 8H), 2.2-2.8 (m, 8H), 3.0-3.6 (m, 4H), 4.2 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H), 9.3 (bs,1H), 10.3 (bs,1H), 11.1 (bs,1H).

EXAMPLE 247 [4-(4-(Chloro-phenoxy)phenylsulfanyl]-acetic acid ethyl ester

[0859] A mixture of 4bromo chlIorobenzene (1.92 g, 10 mnmol), (4-Hydroxy-phenylsulfanyl)acetic acid ethyl ester (2.12 g, 10 mmol), sodium hydride (460 mg, 10 mmol) and copper(fl) chloride (500 mg) was refluxed in anhydrous pyridine (50 ml) for 12 hrs. The reaction mixture was carefully quenched with ice cold water and acidified with concentrated HCl. The product was extracted with choroform, washed well with water; dried and concentrated. The product was purified by silica gel column chromatography by eluting with 30% ethyl acetate : hexane. Yield 2.5 g (77%); Colorless low melting solid; MS: 323 (M+H)⁺. Alternatively the title compound may be prepared from 4-(4chloro-phenoxy)benzenethiol and bromo ethyl acetate as described in example 83.

EXAMPLE 248 [(4-Chloro-phenoxy)benzenesulfonyl]-acetic acid ethyl ester

[0860] [4 (Chloro-phenoxy)benzenesulfonyl]-acetic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)phenylsulfanyl]-acetic acid ethyl ester ( 3.23g, 10 mmol) and oxone (10 g). Yield 3.5g (99%); oil; MS: 356EI

EXAMPLE 249 4-[(4chloro-phenoxy)benzenesulfonyl] 1 -methyl-piperidine~carboxylic acid hydroxyamide

[0861] 4-[(4-Chloro-phenoxy)benzenesulfonyl]-1-methyl-piperidinewcarbokylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)benzenesulfonyl]-acetic acid ethyl ester ( 2.0g, 5.6mmol) and mechlorethanmine hydrochloride (Aldrich), (1.9g, lOmmol). Yield 2g (81%); brown oil; MS:438 (M+H)⁺

[0862] 4[-4-(4Chloro-phenoxy)benzenesulfonyl]-1-methyl-piperidine~carboxylic acid was prepared starting from 4[4-(4-chloro-phenoxy)benzenesulfonyl]- 1 -methyl-piperndine4 carboxylic acid ethyl ester (4.3 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH ( 100 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5g (86%); white solid; mp 185° C.; MS:410(M+H)⁺

[0863] Starting from 4-[(4-chloro-phenoxy)benzenesulfonyl]- -methyl-piperidine-4-carboxylic acid (1.0 g, 2.4 imol) and following the procedure outlined in example 83, 460mg of 4-[4-(4-chloro-phenoxy)benzenesulfonyl] 1-methyl-piperidineAcarboxylic acid hydroxyamide was isolated as a HCl salt, a white powder. Yield 41%; mp 52 ° C.; MS: 426 (M+H)⁺; ¹H NMR (300 MHz, DMSO-dd: o 1.3 (s, 3H), 2.2 - 2.9 (m, 6H), 3.5 (bd, 2H), 7.2 -7.9 ( m, 8H), 8.1 (s, 1H), 11.0 (bs, 1H).

EXAMPLE 250 4-E[(4-chloro-phenoxy)benzenesulfonyl] 1 -ethyl-piperidine-4-carboxylic acid hydroxyamide

[0864] 4-(4-Chloro-phenoxy)benzenesulfonyl]-1-ethyl-piperidine~carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)benzenesulfonyl]-acetic acid ethyl ester (4 g, 11.3 mmol) and ethyl-bis-(2-chloro-ethyl)amine (2.32 g, 16.9 mmol). Yield 3.36 g (66%); brown oil; MS: 452.0 (NM+H)⁺4-[4-(4-Chloro-phenoxy)benzenesulfonyl]-1-ethyl-piperidinefcarboxylic acid was prepared starting from 4-[4-(4-chloro-phenoxy)benzenesulfonyl]- 1 -ethyl-piperidine~carboxylic acid ethyl ester (3.02 g, 6.7 mmol) dissolved in THF:methanol (3: 1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.8 g (65%); white solid; mp 184° C.; MS: 423.9 (M+H)⁺

[0865] Starting from 4-[(4-:4:hloro-phenoxy)benzenesulfonyl]-1-ethy'l-piperidine-4-carboxylic acid (1.75 g, 4.14 mmol) and following the procedure outlined in example 83, 650 mg of 4-[4-(4-chloro-phenoxy)benzenesulfonyl] -ethyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%; mp 158 ° C.; MS: 438.9 (M+H)⁺; ¹H N (300 MHz, DMSO-d₆): 3 1.78 (t, J=7.23 Hz, 3H), 2.23-2.27 (m, 2H), 2.51-2.73 (m, 4H), 04 (m, 2H), 3.81 (d, J=24 Hz, 2H), 7.16-7.27 (m, 4H), 7.50-7.57 (m, 2H), 7.76 (d, J=7 z, 2H), 9.34 (s, 1H), 9.85 (s, 1H).

EXAMPLE 251

[0866] 1-Butyl4[4 chloro-phenoxy)beazenesulfonyl]-piperdinecarboxylic acid hydroxyamide 1-Butyl [(4chloro-phenoxy)benzenesulfonyl]-piperidine carboxyic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)benzenesulfonyl]-acetic acid ethyl ester (6 g, 18.3 mmol) and butyl-bis-(2-chloro-ethyl)aine (5.2 g, 22 mmol). Yield 3.3 g (38%); yellow oil; MS: 480 (M+H)'1-Butyl[4-(4-chloro-phenoxy)benzenesulfonyl]-piperidinecarboxylc acid was prepared starting from 1-butylt[4-(4-chloro-phenoxy)benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (3.3 g, 6.9 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.08 g (67%); white solid; mp 201° C.; MS: 451.9 (hi+H)⁺

[0867] Starting from 1-butyl-4-[4-(4-chloro-phenoxy)benzenesulfonyl]-piperidine-4 carboxylic acid (2 g, 4.43 mmol) and following the procedure outlined in example 83, 630 m,g of l-butyl+[4 (4chiloro-phenoxy)benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a HC₁ salt, a white solid. Yield 31%; mp 212 ° C.; MS: 466.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 8 0.87 (t, J=7.3 Hz, 3H), 1.32 (m, 2H), 1.60 (m, 2H), 2.21 (m, 2H), 2.50 (m, 2H), 2.70 (q, 2H), 3.00 (m, 2H), 3.57 (d, 2H), 7.16-7.26 (m, 4H), 7.49-7.56 (m, 2H), 7.77 (d, J 9 Hz, 2H), 9.34 (s, 1H), 10.13 (s, 1H).

EXAMPLE 252 1-Benzyl-4-[4-(4-chloro-phenoxy)benzenesulfonyl]-piperidinetcarboxylic acid hydroxyamide

[0868] 1-Benzyl-4[4-(4chloro-phenoxy)benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting, from [4-(4-chloro-phenoxy)benzenesulfonyl]-acetic acid ethyl ester (6 g, 16.9 mmol) anid bis-(2-chloro-ethyl)benzyl amine (6.44 g, 24 mmol). Yield 2.21 g (25%); yellow oil; MS: 513.9 (M+H)⁺1-Benzyl-4[4-(4chloro-phenoxy)benzenesulfonyl]-piperidinencarboxylic acid was prepared starting from 1-benzyl4-(4chloro-phenoxy)beinenesulfonyl]-piperidine 4 carboxylic acid ethyl ester (2.11 g, 4.1 inmol) dissolved in ThF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.11 g (56%); white solid; mp 201 ° C.; MS: 485.9 (M+W

[0869] Starting from 1-benzyl-4-[4-(4-chloro-phenoxy)benzenesulfonyl]-piperidine-4-carboxylic acid (1 g, 2.06 mmol) and following the procedure outlined in example 83, 430 mg of 1-benzyl [(4-chloro-phenoxy)benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCl salt, an off white solid. Yield 39%; mp 90.4 ° C.; MS: 500.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-dd: 6 2.18-2.30 (m, 2H), 2.73-2.81 (m, 4H), 3.36 (d, 2H), 4.28 (d, J=4.5 Hz, 2H), 7.15-7.25 (m, 4H), 7.43-7.48 (m, 3H), 7.51-7.56 (m, 4H), 7.74 (d, J=9 Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).

EXAMPLE 253 [4-(3-methyl-butoxy)phenylsulfanyl]-acetic acid ethyl ester

[0870] To stirred solution of (4-Hydroxy-phenylsulfanyl)acetic acid ethyl ester (2.12 g, 10 mmol), K₂CO₃ (anhydrous, 10 g) and 1-bromo-3-methyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with :chloroform; washed well with water and concentrated. The crude product obtained was taken to next step with out purification. Yield 2.7 g (94%); (M+H)⁺-283.

EXAMPLE 254 [4-(3-methyl-butoxy)phenylsulfonyl]-acetic acidsethyl ester

[0871] [4-(3-methyl-butoxy)phenylsulfonyl]-acetic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)phenylsulfanyl-1-acetic acid ethyl ester (2.8 g, 10 mmol) and oxone (10 g). Yield 3.Og ( 99%); oil; MS: 3 14EI (M+H)⁺

EXAMPLE 255 1-Benzyl-4-[4-(3-methyl-butoxy)benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide

[0872] 1-Benzyl-4[(3-methyl-butoxy)benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 mmol) and bis-(2-chloro-ethyl)benzyl amine (6.44 g, 24 m=ol). Yield 8 g (84%); yellow oil; MS: 474 (M+H)⁺1-Benzyl-4fs(3-methyl-butoxy)benzenesulfonyl]-piperidineAcarboxyhic acid was prepared starting from 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.7 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3 g (67%); white solid; mp 182 ° C.; MS: 446 (M+H)⁺

[0873] Starting from 1-Benzyl-4[4-(3-methyl-butoxy)benzenesulfonyl]-piperidineAcarboxylic acid (2.2 g, 5 nmol) and following the procedure outlined in example 83, 1.82 g of l-BenzylA.[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCl salt, an off white solid. Yield 73%; mp 106 ° C.; MS: 498 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 0.8 (d, 6H), 1.5 (m,1H), 1.6-2.0 (m, 6H), 2.73-2.81 (m, 4H), 3.5 (d, 2H), 4.28 (d, J=4.5 Hz, 2H), 7.15-7.25 (m, 4H), 7.43-7.48 (m, 3H), 7.51-7.56 (m, 4H), 7.74 (d, J=9 Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).

EXAMPLE 256 1-Butyl4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carbxylic acid hydroxyamide

[0874] 1-Butyl4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-chloro-ethyl)amine (5.2 g, 22 mmol). Yield 7 g (79%); yellow oil; MS: 440 (M+H)⁺1 -Butyl4[(3-methyl-butoxy)benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Butyl4[(3-methyl-butoxy)benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.4 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.2 g (77%); white solid; mp 188 ° C.; MS: 412 (M+H)⁺

[0875] Starting from 1-Butyl4f(3-methyl-butoxy)benzenesulfonyl]-piperidine-4-carboxylic acid (2.0 g, 5 mmol) and following the procedure outlined in example 83, 1.6 g of 1-Butyl4[4-(3-methyl-butoxy)benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCl salt, an off white solid. Yield 69%; mp 201 ° C.; MS: 464 (M+H)⁺.

EXAMPLE 257 [4-(2-Ethyl-butoxy)phenylsulfanyl]-acetic acid ethyl ester

[0876] To stirred solution of (4-Hydroxy-phenylsulfanyl)acetic acid ethyl ester (2.12 1, 10 mmol), K₂CO₃ (anhydrous, 10 g) and 1-bromo-2-ethyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step without purification. Yield 2.8 g.(94%); (M+H)⁺-297.

EXAMPLE 258 [4-(2-Ethyl-butoxy)phenylsulfonyl]-acetic acid ethyl ester

[0877] [4-(2-Ethyl-butoxy)phenylsulfonyl]-acetic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(2-ethyl-butoxy)phenylsulfanyl]-acetic acid ethyl ester (2.96 g, 10 rninol) and oxone (10 g). Yield 3.1g ( 99%); oil; MS: 329EI (M+H)⁺.

EXAMPLE 259 1-Benzyl-4[4-(2-ethyl-butoxy)benzenesulfonyl]-piperidine~carboxylic acid hydroxyanide

[0878] 1-Benzyl-4[4-(2-ethyl-butoxy)benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [>(2-ethyl-butoxy)phenylsulfonyl]-acetic acid ethyl ester (6.4 g, 20 mnol) and bis-(2-chloroethyl) benzyl amine (6.44 g, 24 mmol). Yield 8 g (82%); yellow oil; MS: 488 (M+H)'

[0879] 1-Benzyl([4-2ethyl-butoxy)benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Benzyl-4-[4(2ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.8 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4 g (87%); Semi solid; MS: 460 (M+HI)

[0880] Starting from 1-Benzy4[s(2ethyl-butoxy)benzenesulfonyl]-piperidine-4fcarboxylic acid (2.2 g, 5 mmol) and following the procedure outlined in example 83, 1.02 g of 1-Benzyl-4[$ (2-ethyl-butoxy)benzenesulfonyl]-piperidine~carboxylic acid hydroxyamide was isolated as a HC₁ salt, an off white solid. Yield 40%; mp 114 ° C.; MS: 512 (M+H)⁺.

EXAMPLE 260 4-(4butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidine-4-carboxylic acid hydroxyamide

[0881] 4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidine~carboxylic acid ethyl ester was prepared according to the eneral method outlined in example 83 starting, from (4butoxy-benzenesulfonyl)acetic acid ethyl ester (20 g, 77.5 mmol) and bis-(2-chloro-ethyl)(3-methoxy-benzyl)amine (34 g, 116 mmol). Yield 9.53 g (25%); brown oil; MS: 490.2 (M+H)⁺

[0882] 4-(4Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidinencarboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidineff carboxylic acid ethyl ester (2.61 g, 5.34 mmol) dissolved in THF:methanol (3:1 150 mI) and 10 N NaOH (15 ml). The resulting reactionr mixture was worked up as'outlined in example 83. Yield 1 g (41%); brown solid; mp 175° C.; MS: 462.0 (M+H)⁺

[0883] Starting from 4-(4butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidine~carboxylic acid (900 mg, 1.95 nmmol) and following the procedure outlined in example 83, 200 mg of 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidineA arboxylic acid hydroxyamide was isolated as a HCl salt, a brown powder. Yield 20%; mp 137 ° C.; MS: 477.0 (iM+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 8 0.96 (t, J=7.11 Hz, 3H), 1.48 (m, 2H), 1.73 (m, 2H), 2.27 (m, 2H), 2.47 (m, 2H), 2.78 (m, 2H), 3.35 (m, 2H), 3.77 (s, 2H), 4.08 (t, J=6.3 Hz, 3H), 4.32 (s, 2H), 7.03 (t, 2H), 7.15 (m, 3H), 7.36 (t, J=7.8 Hz, 1H), 7.64 (d, J=9 Hz, 2H), 9.36 (s, 1H), 10.22 (s, 1H).

EXAMPLE 261 4-(4-Methoxy-benzenesulfonyl) 1-iophen-2-yl-benzyl)piperidine-4arboxylic acid hydroxyamide

[0884] 4-(4-Methoxy-benz enesulfonyl) 1 -(4-thiophen-2-yl-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared starting from 1-(4-Bromo-benzyl)4-(4-methoxy-benzensulfonyl) piperidine-4-carboxylic acid ethyl ester (3 g, 6.05 mmol) and 2-(tributylstannyl)thiophene (6.8 g, 18.14 mmol) in the presence of tetrakis palladium (0) in boiling tolune. Yield 1.58 , (52%); brown solid; mp 130° C.; MS: 500 (M+H)⁺4-(4-Methoxy-benzenesulfonyl) 1-(4-thiophen-2-yl-benzyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl) 1-(4-thiophen-2-yl-benzyl)piperidine-carboxylic acid ethyl ester (1.3 g, 2.61 mmol) dissolved in THF:methanol (3:1 I50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 950 mg (77%); brown solid; mp 235° C.; MS: 471.8 (M++) Starting from 4-(4-methoxy-benzenesulfonyl)-1-(4thiophen-2-yl-benzyl)piperidine-4 carboxylic acid (920 mg, 1.95 inmol) and following the procedure outlined in example 83, 510 mg of 4-(4-methoxy-benzenesulfonyl) 1-(4-thiophen-2-yl-benzyl)piperidine-4fcarboxylic acid hydroxyamide was isolated as a HCl salt, a brown solid. Yield 50%; mp 166 ° C.; MS: 486.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): o 2.12-2.21 (m, 2H), 2.50 (m, 2H), 2.78 (m, 2H), 3.39 (m, 2H), 3.87 (s, 3H), 4.29 (d, 2H), 7.17 (m, 3H), 7.54-7.75 (m, 8H), 9.36 (s, 1H), 10.07 (s, 1H)

EXAMPLE 262 4(4-methoxy-benzenesulfonyl)-1-(4pyridin-2-yl-benzyl)piperidine-4-carboxylic acid hydroxyamide

[0885] 4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 261. Starting from 1-(4-Bromo-benzyl)4-(4-methoxy-benzensulfonyl)piperidinetcarboxylic acid ethyl ester (4.65 g, 9.38 mmol) and 2-(tributylstannyl)pyridine (12.08 g, 32.8 nimol). Yield 2.79 g (60%); brown oil; MS: 495.1 (M+H)'

[0886] 4-(4-Methoxy-benzenesulfonyl) 1 -(⁴⁻pyridin-²-yl-benzyl)piperidine 4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)l4pyrdi-2-yl-benzyl)piperidineX carboxylic acid ethyl ester (1.83 g, 3.7 mmol) dissolved in TB:methanol (3:1 150 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.38 g (80%); off white solid; mp 217° C.; MS: 466.9 (M+H)⁺

[0887] Starting from 4-(4-methoxy-benzenesulfonyl)-1-(4pyridin-2-yl-benzyl)piperidinew carboxylic acid (1.32 g, 2.83 mmol) and following the procedure outlined in example 83,480 mg of 4-(4-metho xy-benzenesulfonyl) 1-(pyrdin-2-yl-ben yl)piperdine4aoxylic acid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%; mp 214 ° C.; MS: 482.0 (M+H)⁺; ¹H NMR (300 MH, DMSO-d,): 8 2.30 (m, 2H), 2.80 (m, 2H), 3.42 (d, J=12.5 Hz, 2H), 3.75 (m, 2H), 3.88 (s, 3H), 4.36 (s, 2H), 7.15 (d, I=8.9 Hz, 2H), 7.59-7.74 (m, 4H), 7.84-7.95 (m, 3H), 8.55 (d, J=8.1 Hz, 1H), 8.79 (s, 1H), 9.14 (s, 1H), 10.68 (s, 1H),

EXAMPLE 263 1-(3,4-Dichlorobenzyl)A(4-butoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

[0888] 4-(4Butoxy-benzenesulfonyl)-1-(3,4Zichloro-benzyl)piperidinencarboxylic acid ethyl ester was prepared according to the general method outlined in example 83. Starting from (4butoxy-benzenesulfonyl)acetic acid ethyl ester (13.2g 44 muol) (S,4dichloro-benzyl)bis-(2-chloro-ethyl)amine (14.3g, rmol). Yield 14.1; (60%), white solid, MP 86° C.; MS: 527.9 (MI+H)'1-(3,4-dichlorobenzyl)4-(4-butoxy-benzenesulfonyl)piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(3,Sdichloro-benzyl)piperidineX carboxylic acid ethyl ester (14.0 g, 26.5 mmol) dissolved in THF:Methanol (100: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.87 (60%); off white solid; mp 239 ° C.; MS: 501.9 (M+H)⁺

[0889] Starting 1-(3,4dichlorobenzyl)4-(4-butoxy-benzenesulfonyl)piperidinefcarboxylic acid (7.7g, 15.5 mmol) and following the procedure outlined in example 83, 4.05g of 1-(3,4-dichlorobenzyl)4-(4butoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyanmide was isolated as a HCl salt, white solid. Yield 48%; mp 256.8 ° C.; MS: 514.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 3 0.94 (t, 3H), 1.38-1.48 (q,2H), 1.68-1.75 (q, 2H), 2.27 (m, 4H),2.72 (m, 2H), 4.10 (t, 2h), 4.24 (s, 2H), 7.12-7.15 (d, J=8.9, 2H), 7.51-7.53 (d, J=8.1, 1H), 7.63-7.65 (d, J=8.8, 2H), 7.72-7.75 (d, J=9.9, 2H), 7.87 (s, 1H), 9.36 (s, 1H), 10.5 (s, 1H), 11.2 (s, 1H)

EXAMPLE 264 [s(4-Chloro-benzyloxy)benzenesulfonyl]-1-methylpiperidine-4f carboxylic acid hydroxide

[0890] [(4-Chloro-benzyloxy)benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [(4-chloro-benzyloxy)benzenesulfonyl]-acetic acid ethyl ester (13.79g, 37 mmol) and 4-(4 chloro-ben:zyloxy)bis-(2chloro-cthyl)amine (8.7g, 45 mmol). Yield 10.9 (65%); brown oil; MS:451.9 (M+H)⁺

[0891] [4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidinetcarboxylic acid was prepared starting from [(4-Chloro-benzyloxy)benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 75 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.9g (50%); off white solid; MS: 426.2 (M+H)⁺

[0892] Starting from [4-(4-Chloro-benzyloxy)benzenesulfonyl-1-rnethylpiperidine-4-carboxylic acid (4.9g, 12 mmol) and following the procedure outlined in example 83, 1.2g of [4-(4-Chloro-benzyloxy)benzenesulfonyl]-1-methylpiperidine-4carboxylih acid hydroxamide was isolated as a HC₁ salt, off white solid. Yield 24%; mp 117.8 ° C.; MS: 438.9 (M+H)⁺; ¹H NIR (300 MHz, DMSO-d₆): 5 2.2 (m, 2H), 2.49 (m, 4H), 2.5 (s, 3 H), 2.6 (mi, 2H), 5.2 (s, 2H), 7.25-7.23 (d, t=8.7, 2H), 7.5 (d, t=2.7, 4H), 7.68-7.71 (d, t=9.6, 2H), 9.33 (s, 1H), 10.11 (s, 1H)

EXAMPLE 265 4(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)piperidine-4 carboxylic acid hydroxamide

[0893] 4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)piperidine~carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 44 butoxy-benzenesulfonyl)acetic acid ethyl ester (10.1 g, 34 mmol) and 1-(3-phenoxy-benzyl) bis-(2-chloro-ethyl)amine (18g, 50 mmol). Yield 8.9 (49%); brown oil; MS: 552.1 (M+H)⁺

[0894] 4-(4-Butoxy-benzenesulfonyl)I13-phenoxy-benzyl)piperidine-4arboxylic acid was prepared starting from 4-(4butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)piperidine-4 carboxylic ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 5.0 g (76%); off white solid; MS: 524.3 (M+H)⁺

[0895] Starting from (4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)piperidine-4-carboxylic acid (5.9 g, 11 mmol) and following the procedure outlined in example 83, 0.39g of 4-(4 butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)piperidine-4-carboxylic acid hydroxamide was isolated as a HCl salt, tan solid. Yield 1 1%; mp 92.5 ° C.; MS: 539.1 (M+H)⁺; tH NMR (300 MHz, DMSO-d6): 5 -0.93-0.97 (t, J=3.6, 3H), 1.49 (m, 2H), 1.73 (m, 2H), 2.51 (m, 4H), 4.09 (t, 2H), 4.29 (bs, 2H), 7.06-7.10 (d, J=12, 2H), 7.13-7.15 (m, 3H), 7.39-7.42 (d, 2H), 7.63-7.66 (d, 2H), 9.50 (s, 1H), 9.98 (s, 1H)

EXAMPLE 266 [(4-Chlorobenzyloxy)benzenesulfonyl]- 1-(4-methylbenzyl)piperidine-4 carboxylic acid hydroxamide

[0896] [4-(4-Chloro-benzyloxy)benzenesulfonyl]- 1-(4methylbenzyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [1-(4-chloro-benzyloxy)benzenesulfonyl]-acetic acid ethyl ester (5.47g, 15 mmol) and 1-(4 methyl-benzyl)bis-(2-chloraethyl)amine (5.23g, 18 mmol). Yield 8.0 (96%); brown oil; MS: 542.0 (M+H)

[0897] [4-(4-Chloro-benzyloxy)benzenesulfonyl]- 1-(4methylbenzyl)piperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)benzenesulfonyl]- 1-(4-methylbenzyl)piperidine-4 carboxylic acid ethyl ester (7.9 g, 124 mmol) dissolved in THF:Methanol (50: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.6g (61%); off white solid, mp 204 ° C.; MS: 514.2 (M+H)⁺

[0898] Starting from [4-(4Chlor~benyloxy)benzenesulfonyl]- 1-(4methylbenzyl)piperidineX carboxylic acid (4.2g, 8 mmol) and following the procedure outlined in example 83, 1.3g of [4-(4Chloro-benzyloxy)benzenesulfonyl]-1-(4methylbenzyl)piperidinetcarboxylic acid hydroxamide was isolated as a HCl salt, yellow solid. Yield 29%; mp 172 ° C.; MS: 528.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d): 3

EXAMPLE 267 4(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)piperidineX carboxylic acid bydroxamide

[0899] 4-(4-Butoxy-benzenesulfonyl)-1-(methylbenzyl)-piperedinearboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting 4-(4-Butoxy-benzenesulfonyl)-acetic acid ethyl ester (5.47g, 15 mmol) and 1-(4methyl-benzyl)-bis2-chloro-ethyl)-amine (15.3g, 51 mmol). Yield 10.1 (57%); white solid, MP 93° C.; MS: 474.1 (M+H)⁺

[0900] 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylben:zyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4methylbenzyl)-piperidine~carboxylic ethyl ester (10.0 g, 22 nmol) dissolved in THF:Methanol (50:50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.2g (72%); off white solid, mp 244 ° C.; MS: 446.3 (iM+H)⁺

[0901] Starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4methylbenzyl)-piperidine-4-carboxylic acid (6.6g, 1.5 mmol) and following the procedure outlined in example 83, 2.06g of 4-(4-Butoxy-benzenesulfonyl)-l -(methylbenzyl)-piperidine-4arboxylic, acid hydroxamide was isolated as a HCl salt, yellow solid. Yield 28%; mp 137 ° C.; MS: 461.3 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 3 0.91-0.964 (t, J=7.3, 3H), 1.41 (m, 2H), 1.70 (m, 4H), 1.79 (t, s, 3H), 2.52 (m, 2H), 2.76 (m, 2H), 3.33 (bd, 2H), 4.10 (t, 2H), 4.22 (d, 2H), 7.12-7.14 (d, J=8.7, 2H), 7.25-7.28 (d, J=8.1, 2H), 7.42-7.45 (d, J=7.8, 2H), 7.63-7.65 (d, J=8.7, 2H), 10.31 (s, IEI), 10.75 (bs, 1H)

EXAMPLE 268 4-(4-Butoxy-benzenesulfonyl)-1-(4cyano-benzyl)-piperidine hydroxamide carboxylic acid hydroxamide

[0902] 4-(4-Butoxy-benzenesulfonyl)-1-(4cyano-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 staring 4-(4-Butoxy-benzenesulfonyl)-acetic acid ethyl ester (5.29g, 17.6 mmol) and 1-(4cyano-benzyl)-bis-(2-chloro-ethyl)amine

[0903] (6.19g, 21 mmol). Yield 6.8g (80%); tan oil; MS: 485.0 (M+H)⁺4-(4-Butoxy-benzenesulfonyl)-1-(4cyanobenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4yanbenzyl)-piperidineAfcarboxylic ethyl ester (10.0 g, 124 mmol) dissolved in THF:Methanol (75: 50 ml) and I0 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield .7g (11%); off white solid; MS: 456.0 (M+H)⁺

[0904] Starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4cyanobenzyl)-piperidine~carboxylic acid (600 g, 1.2 mmol) and following the procedure outlined in example 83, .21g of 4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxamide was isolated as a HCl salt, off white solid. Yield 34%; mp 241.6 ° C.; MS: 472.0 (M+H)⁺; ¹H i iR (300 MHz, DMSO-d₆): 5 .915-.964 (t, J=7.2, 3H), 1.51 (q, 2H),-,1.75 (q, 2H), 2.27 (m, 2H), 2.49 (m, 4H), 4.11-4.19 (t, 2H), 4.37 (s, 1H), 7.12-7.15 (d, J=8.7, 2H), 7.63-7.66 (d, J=9, 2H), 7.72-7.74 (d, J=7.8, 2H), 9.36 (s, 1H), 10.23 (s, 1H), 11.16 (s, 1H)

EXAMPLE 269 4-(4-Butoxy-benzenesulfonyl)-1-pyridintylmethyl-piperidine-4f carboxylic acid hydroxamide

[0905] 4-(4-Butoxy-benzenesulfonyl)-1-pyridinffylmethyl-piperidine~carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting with 4-(4 Butoxy-benzenesulfonyl)-acetic acid ethyl ester (6.0 g, 20.0 mmol) and pyridin-4-ylmethyl-bis-(2-chloro-ethyl)-armine.

[0906] (4.89 g, 21 mmol). Yield 4.5g (48%); Brown oil; MS: 461.0 (M+H)⁺

[0907] 4(4-Butoxy-benzenesulfonyl)-1-pyridinfylmethyl-piperidine-4-carboxylic acid was prepared starting from (4-Butoxy-benzenesulfonyl)-1-pyridin ylmethyl-piperidine b ooxylic acid ethyl ester (3.0 g, 6.5 mmol) dissolved in TH:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2g (42%); off white solid; MS: 433.0 (M+H)⁺

[0908] Starting from 4-(4-Butoxy-benzenesulfonyl)-1-pyridinfylmethyl-piperidine-4-carboxylic acid (0.864 mg, 2.0 mmol) and following the procedure as outlined in example 83, 600 mg of 4 (4-Butoxy-benzenesulfonyl)-1-pyridin~ylnethyl-piperidineAcarboxylic acid hydroxyamide was isolated as a HCl salt, off white solid. Yield 67%; mp 118 ° C.; MS: 447.9 (M+H)⁺; 1H NMR (300MHz, DMSO-d6): dO.94 (t, 3H), 1.11 (t, 1H), 1.23 (t, 1H), 1.44 (m, 1H), 1.73 (m, 1H),2.34 (m, 2H), 2.78 (m, 2H), 3.10 (m, 2H), 3.38 (m, 2H), 4.08 (t, 2H), 4.42 (br s, 2H), 7.13 (d, 2H), 7.64 (d, 2H), 7.94 (d, 2H), 8.82(d, 2H), 11.2 (br s, 1H), 11.4 (br s, 1H).

REFERENCES

[0909] 1 Rickter, L. S.; Desai, M. C. Tetrahedron Letters, 1997, 38, 321-322.

[0910] The subject compounds of the present invention were tested for biological activity according to the following procedures.

In Vitro Gelatinase Assay

[0911] The assay is based on the cleavage of the thiopeptide substrate ((Ac—Pro—Leu—Gly(2 mercapto-4 methyl-pentanoyl)—Leu—Gly—OEt), Bachem Bioscience) by the enzyme, gelatinase, releasing the substrate product which reacts colorimetrically with DTNB ((5,5′-dithio-bis(2-nitro-benzoic acid)). The enzyme activity is measured by the rate of the color increase. The thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the D'TNB is dissolved in 100% DMSO as a 100 mM stock and stored in dark at room temperature. Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl₂) before use. The stock of human neutrophil gelatinase B is diluted with assay buffer (50 rmM HEPES pH 7.5, 5 MM CaC₁₂, 0.02% Brij) to a final concentration of 0.15 nLM.

[0912] The assay buffer, enzyme, DTNB/substrate (500 ,uM final concentration) and vehicle or inhibitor are added to a 96 well plate (total reaction volume of 200w) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader.

[0913] The increase in OD405 is plotted and the slope of the line is calculated which represents the reaction rate.

[0914] The linearity of the reaction rate is confinmed (r²>0.85). The mean (x±sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's multiple comparison tesl Dose-response relationships can be generated using multiple doses of drug and IC₅o values with 95% CI are estimated using linear regression (IPRED, HTB).

[0915] References: Weingarten, H and Feder, J., Spectrophotometric assay for vertebrate collagenase, Anal. Biochem. 147, 437440 (1985).

In Vitro Collarenase Assay

[0916] The assay is based on the cleavage of a peptide substrate ((Dnp—Pro—Cha—Gly—Cys(Me)—His—Ala—Lys (NMa)—NH2), Peptide International, Inc.) by collagenase releasing the fluorescent NMa group which is quantitated on the fluorometer. Dnp quenches the NiMa fluorescence in the intact substrate. The assay is run in HCBC assay buffer (50 nuM HEPES, pH 7.0, 5 nM Ca⁺², 0.02% Brij, 0.5% Cysteine), with human recombinant fibroblast collagenase (truncated, mw=18,828, WAR, Radnor). Substrate is dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase is stored frozen in buffer in 25 pM aliquots. For the assay, substrate is dissolved in HCBC buffer to a final concentration of 10 IM and collagenase to a final concentration of 5 nM. Compounds are dissolved in methanol, DMSO, or HCBC. The methanol and DMSO are diluted in HCBC to<1.0%. Comnpounds are added to the 96 well plate containing enzyme and the reaction is started by the addition of substrate.

[0917] The reaction is read (excitation 340 rum, emission 444 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate.

[0918] The linearity of the reaction rate is confirmed (r²>0.85). The mean (x +sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generated using multiple doses of drug and IC₅₀ values with 95% CI are estimated using linear regression (IPRED, Hm) .

[0919] References: Bickett, D. M. et al., A high throughput fluorogenic substrate for interstitial collagenase (MMP-1) and gelatinase (MMP-9), Anal. Biochem. 212,58-64 (1993).

Procedure for Measuring TACE Inhibition

[0920] Using 96-well black microtiter plates, each well receives a solution composed of 10 μL TACE (Immunex, final concentration 1 pg/mL), 70 μL Tds buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM), and 10 μL of test compound solution in DMSO (final concentration 1 μM, DMSO concentration<1%) and incubated for 10 minutes at room 1o temperature. The reaction is initiated by addition of a fluorescent peptidyl substrate (final concentration 100 μM to each well and then shaking on a shaker for 5 sec. The reaction is read (excitation 340 nm, emission 420 nm) for 10 mnin. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate.

[0921] The linearity of the reaction rate is confirmed (r²>0.85). The mean (xjsem) of the control rate is calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generate using multiple doses of drug and IC₅₀ values with 95% CI are estimated using linear regression

[0922] The results obtained following these standard experimental test procedures are presented in the following table. IC 50 (nM or % inhibition at 1 micromolar or 10 micromolar (*)) Example MMP 1 MMP 9 MMP 13 TACE  1 NT 559.6 193.3 31.62%  2 NT 10.50% 0% 403  3 NT 308.9 169.4 27.43%  4 371 22.20% 17.10% 21%  5 NT 7.7 4.7 25%  6 267 21.4 15.6 40.43%  7 844 72.9 42.1 33%  8 NT 346 307.9 47%  9 313 107 NT 20.30%  10  8% 128 64 54.75%  11 18.80% 2925 319 942  12 100 10.8 11 15.50%  13 239 11 14 626  14 158 23 8 17.18%  15 285 17 4 137  16 325 9 24 180  17 238.6 8.9 1.4 41.00%  18 540 18.9 11.5 29.2%  19 446 95.8 4.8 33.1%  20 423 14.6 18.7 31%  21 318 13.2 15.3 39%  22 219 3.2 2.5 30%  23 593 7.9 4.0 40.6%  24 413 20.9 31.3 47.5  25 262 26.7 8.0 NT  26 304.6 6.3 3.2 34.6  27 629 106 30.1 NT  28 761 3.1 2.0 30.6%  29 297 4.3 3.6 41%  30 397 8.1 5.7 25.2%  31 162 15.2 5.7 688  32 13.7 3.7 1.0 NT  33 318 53.9 18.4 23.9%  34 519.8 34.7 26.1 28.1%  35 455.8 233.6 48.2 44.9  36 622 83.8 20.7 826  37 9% 31.6% 14.3% 87  38 48.3% 1.7% 5.8% 55.1%  39 29.4% 35.2% 26.6% 69.4  40 583 197 14 160  41 100 10.8 11 15.50%  42 262 50.9 6.2 36.5  43 66.1% 34.7% 55.5% 46.6%  44 47.1% 36.9% 39.5% 14.9%  45 49% 48.6% 36.7% 20.4%  46 78.9% 79.12% 84.7% 1.4%  47 17.1% 12.9% 7.12% 3.3%  48 99.1% 79.1% 85.4% 51.1%  49 10.1% 23.7% 54.6% NT  50 51.1 58.4 10.6 NT  51 178.1 10.4 13.1 48.14%  52 139.3 7.9 9.1 NT  53 647.9 27.80% 188 52.57%  54 110 66 21 55.10%  55 303 10 7 21.70%  56 299 16 12 65%  57 258 332 191 16.57%  58 211 35 39 7.70%  59 30.20% 447 141 24.86%  60 NT 184 NT 23.60%  61 258 38 22 17.21%  62 522 174 43 669  63 156 9 3 203  64 40.90% 25.60% 36.70% 29.70%  65 1000 63 13 42.21%  66 1600 131 226 42.33%  67 364 2.3 43.7 690  68 297 29 27 522  69 574.5 120.2 90 41.32%  70 1139 88.80% 127 764  71 1000 63 13 42.21%  72 117 11 1 51.64%  73 300 141 12 20.17%  74 138.1 9.2 4.3 47.86%  75 672.3 83.4 32.7 23.77%  76 805 NT 500 NT  77 205.5 NT 170 NT  78 262 560 34 24.58%  79 25 0.54 0.4 805  80 22.1% 26% 63.6% 191  81a 2036 230.9 43.9 27.1  81b 3765 154 15.7 228  82 237.6 19.4 5.1 34.5%  83 492 10.2 2.0 229  84 519 8.8 2.0 213  85 450 5.8 1.5 115  86 494 16.8 1.5 222  87 368 5.0 1.6 170.7  88 1329 12.8 3.1 610  89 1389 38.6 7.0 49%  90 598 10.3 2.2 71.9  91 1929 13.3 10.8 503  92 59.6% 649 148 9.7  93 56.3% 452 38 15.8%  94 2640 138 28.6 22.9  95 3681 364 33.1 25.4%  96 4437 374 33.8 18.1  97 5109 484 43.7 20.20%  98 2383 3.8 1.2 154  99 656 16.2 2.4 250 100 4729 19.1 5.3 39.5% 101 642 12.3 2.1 197 102 662 33.7 1.9 53% 103 1306 45.1 8.8 470 104 2610 3.1 1.4 208 105 1214 44.2 4.1 50.2% 106 3788 5.1 0.9 631 107 629 26.8 2.5 293 108 2896 5.4 1.7 270 109 393 2.7 2.5 386 241 48.2%* 2.7 15.8 277 242 1950 2 1.3 581 243 2181 1.9 1.5 506 244 3417 9.8 1.5 594 245 7062 43.4 2.2 51.95%* 246 50.30%* 28.3 2.4 880 249 1412 2 1.6 270 250 1717 1.6 0.8 413 251 1067 0.8 0.9 301 252 801 1.1 0.9 278 255 2558 3.6 1.5 565 256 10000 7.2 2.9 43.01%* 259 3160 14.3 5.3 39%* 260 1495 2.9 1.3 272 261 513 10.9 2.7 273 262 422 6.1 2.3 298 263 3669 20.3 5.2 57.70%* 264 4293 2.9 3.1 182 265 1944 9.3 7.8 1037 266 4746 6 5.7 421 267 3620 5.4 2.3 508 268 2292 2.8 1.1 278 269 2071 2.2 1.4 296

[0923] Compounds prpared by solid phase synthesis Data: for Examples 110 to 240 Example No MMP 13% MMP 13% TACE % inhibition inhibition at inhibition at 0.2 0.2 μM at MMP 1 MMP 9 μM (HTS) (manual) 1 mM 110 75 17.6 111 10 40.4 112 50 33.7 113 0 13.1 114 0 0 115 0 0 116 0 9.1 117 7 8.1 118 24 16.7 119 0 7.8 120 31 19.9 121 0 6.1 122 0 3.1 123 0 2.5 124 0 0 125 5 2.3 126 25 10.4 127 47 29.2 128 1.9 mM 213 nM 91 255 nM 19.31 129 90 32.77 130 28 27.9 131 71 20.73 132 71 20.76 133 53 22.04 134 25 −9.31 135 79 42.67 136 89 42.69 137 83 13.35 138 20 5.284 139 8 28.05 140 29 −4.22 141 32 11.76 142 69 54.27 143 53 43.9 144 38 19.7 145 45 2.5 146 68 7.317 147 73 11.95 148 15 43.46 149 13 4.408 150 54 1.818 151 6 5.927 152 9 10.03 153 12 11.8 154 89 13.14 155 31 −18.62 156 23 −2.09 157 19 13.7 158 33 −7.48 159 49 5.852 160 14 −3.57 161 0 12.7 162 13 0 163 84 9.515 164 74 62.69 165 71 73.7 166 9 4.16 167 27 8.961 168 21 3.688 MMP 13% MMP 13 MMP 13 inhib- % inhib- % inhib- TACE ition at ition at ition at % inhib- 36 nM 0.36 mM 3.6 mM TACE ition at (HTS) (HTS) (HTS) IC₅₀ nM 1 mM 169 28 40 72 41.7 170 32 49 90 25.5 171 31 38 48 16.6 172 34 32 42 29.4 173 18 46 56 25.5 174 10 19 40 27.7 175 16 20 37 32.9 176 6 5 16 26.6 177 5 1 9 38.5 178 −10 74 39 26 179 12 32 60 42.7 180 14 19 45 34.4 181 6 35 62 15.7 182 −9 −8 7 28.6 183 −6 12 70 34.6 184 16 24 44 24.8 185 9 0 23 7.21 186 −14 −4 35 19.5 187 −14 −12 20 85.5 188 −27 −24 4 16.2 189 −30 −18 −9 14. 190 −35 −28 −13 38.3 191 −45 −3 22 2.9 192 −32 5 61 33.2 193 −32 −15 56 14.9 194 −17 −8 5 5.4 195 −9 −2 10 27.0 196 −18 1 11 35.7 197 −33 −26 −3 17.8 198 −39 −7 15 17.1 199 −10 −7 30 −1.0 200 37.9 201 50.9 202 10.6 203 32.8 204 7.75 205 84.0 206 89.8 207 −6.3 208 67.7 209 31.2 210 52.2 211 20.7 212 56.0 213 −17.5 214 11.03 215 895 60.12 216 2.49 217 55.1 218 380 68.7 219 7.3 220 256 53.1 221 146 98.9 222 212 89.3 223 226 107.3 224 404 75.0 225 96.6 114.3 226 28 22 28 2.2 227 15 −16 −22 7.3 228 37 28 65 6.8 229 29 17 33 34.4 230 29 31 26 700 72.1 231 23 13 5 41.6 232 30 17 42 20.8 233 33 29 46 19.8 234 26 28 40 18.4 235 59 70 70 48.3 236 44 44 64 35 237 55 65 72 38.2 238 22 11 24 930 54.4 239 54 74 83 45.9 240 48 51 46 40.3

Pharmaceutical Composition

[0924] Compounds of this invention may be adminstered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid

[0925] Applicable solid carrers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

[0926] Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

[0927] Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.

[0928] The compounds of this invention may be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transderrnally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carTier, or a matrix containing the active ingredient Other occlusive devices are known in the literature.

[0929] The dosage to be used in the treatment of a specific patient suffering from a disease or condition in which MMPs and TACE are involved must be subjectively determined by the attending physician. The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles.

[0930] Preferably the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is subdivided in unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefiled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. 

What is claimed is:
 1. A compound according to formula I

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵;, or heteroaryl-(CH₂)₀-6— wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from Q, S, and N and may be optionally substituted with one or two groups selected independently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionally having one or two double bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵; R⁵ is H, C₇-C₁l aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-Cl₂ perfluoro alkyl, S(0)n-C₁-C₆ alkyl, S(0)n-aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SOaryl, -NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂iNHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkI, CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to .10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; R⁶ is H, Cl to C₁₈ alkyl optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, C, to C₆ perfluoro alkyl, S(0)n-C₁-C₆ alkyl S(0)n aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and R⁷ is C₁-Cl 1 aroyl, CZC₆ alkanoyl, C₁-Cl₂ perfluoro alkyl, S(0)n-C₁-C₆-alkyl, S(0)n-aryl where n is 0, 1 or 2; COO—C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO.NR⁶R⁶, SC₂CF₃, SO2NHheteroaryl, SO₂NHCOaryl, CONHSO—C₁-C₆-alkyl, CONHSO₂aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biRhenyl is optionally substituted with one or two groups selected independently from R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C₁-C₆ alkyl, optionally substituted with one or two groups selected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1 wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R⁵; cycloaliyl of 3 to 8 carbon atoms, optionally substituted with one to two groups selected independently from R⁵; saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR⁷, optionally substituted with one to two groups selected independently from R⁵; or heteroaryl-(CH₂)0-₆— wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ pptionally having one or two double bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵; R⁵ is H, F, Cl, Br, I, CN, CHO, C₇-C₁, aroyl, C₂-C₆ alkanoyl, Cl to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆-alkylaMinrC₁ C₆ alkoxy, C₁-C₂-alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyL S(0)n-C₁-C₆ alkyl, S(0)n-aryl where n is 0, 1 or 2; OCOO—C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COO—C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH2, OH, aryl, heteroaryl, C₃ to Cg cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7; wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, aniino, nitro, C₁-C₆ alkyl, Clc₆ alkoxy, or hydroxy; R⁶ is H, C, to C₁₈ alkyl optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, C, to C₆ perfluoro alkyl, S(0)r alkyl or aryl where n is 0, 1, or 2; or COheteroaiyl; wherein heteroaryl is a 5-10 membered mono orbicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and R⁷ is C₇-CII aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl, S(0),-alkyl, S(0)n-aryl where n is 0, 1 or 2; COOalkyl, COaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO2NHheteroaryl, SO₂NHCOaryl, CONHSO₂alkyl, CONHSO₂aryl, aryl, heteroaryl; wherein C₁-C₆ alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; heteroarylalkl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; cycloallylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C₁-C₆ alkyl, optionally substituted with one or two groups selected independently from R⁵; R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹r are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
 3. A compound according to claim 2 wherein R¹ is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or faranyl, optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, halogen; or S(O)_(n)—Cl₆alkyl C₁-C₆ alkoxyaryl or C₁-C₆ alkoxyheteroaryl; A is —S—, O- or —SO₂—; R² and R³, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionally having one or two double bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵; R⁵ is H, C₇-Cl, aroyl, C₂-C₆ alkanoyl, Cl to C₁₂ alkyl,C₂ t6 C₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluorQ alkyl, S,(O) i-C₁-C₆ alkyl, S(0)n-2.5 aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCO0aryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO2aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, wherein C₁₆ alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁₆ alkyl, C₁-C₆ alkoxy, or hydroxy; R⁶ is H, Cl to C₁₈ alkyl optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C alkynyl, Cl to C₆ perfluoro alky, S(0), alkyl or aryl where n is 0, 1 or 2; or COheteroaryl; wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alky, C₁-C₆ alkoxy, or hydroxy; and R⁷ is CCl, aroyl, C₂-C₆ alkanoyl, C₁-Cl₂ perfluoro alkyl, S(0),-alkyl, S(0)n-aryl where n is 0, 1 or 2; COOalkyl, COaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO₂alkyl, CONHSO₂aryl, aryl, or heteroaryl; where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having, 1 to 3 heteroatoms selected independently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; arylalkyl of 7 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R⁵; biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR—C₁-C₆ alkyl, optionally substituted with one or two groups selected independently from R⁵; R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containg an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
 4. A compound according to claim 1 which is 1-benzyl(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof.
 5. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4arboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof.
 6. A compound according to claim 1 which is 1-(3,Sdichlorobenzyl) 4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.
 7. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-(4 methylbenzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.
 8. A compound according to claim 1 which is 4-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.
 9. A compound according to claim 1 which is l-biphenyl1Ayhnethyl,(4-methoxy-benzenesulfonyl)piperidine~carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.
 10. A compound according to claim 1 which is 4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine~carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.
 11. A compound according to claim 1 which is 1-(4bromo-benzyl)4(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof.
 12. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-[4-(2 piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy amide or a pharmaceutically accepted salt thereof.
 13. A compound according to claim 1 which is 1-benzyl4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamde or a pharmaceutical salt thereof.
 14. A compound according to claim 1 which is 4-(4butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 15. A compound according to claim 1 which is 4-(4butoxy-benzenesulfonyl)-1-[3-(2-morpholnyl-1-ylethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 16. A compound according to claim 1 which is 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 17. A compound according to claim 1 which is 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 18. A compound according to claim 1 which is 1-n-butyl(4-butoxy-benzenesulfonyl)-piperidine carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 19. A compound according to claim 1 which is 4-[(4chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof
 20. A compound according to claim 1 which is 4-[4-(4-chloro-phenoxy)-berizenesulfonyl]1-ethyl-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 21. A compound according to claim 1 which is 1-butyl-4-(4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine~carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 22. A compound according to claim 1 which is l-benzylX[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidinefcarboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 23. A compound according to claim 1 which is 1-benzyl4[s(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or apharmaceutical salt thereof.
 24. A compound according to claim 1 which is l-butylA[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 25. A compound according to claim 1 which is 1-benzyl4[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine~carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 26. A compound according to claim 1 which is 4-(4butoxy-benzenesulfonyl)-1-(3-methoxy benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 27. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 28. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 29. A compound according to claim 1 which is 1-(3,Sdichlorobenzyl)4-(4-butoxy-benzenesulfonyl)-piperidine~carboxylic acid hydroxyamide or a pharmaceutical salt thereof.
 30. A compound according to claim 1 which is [4-(4chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.
 31. A compound according to claim 1 which is 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine~carboxylic acid hydroxamide or a pharmaceutical salt thereof.
 32. A compound according to claim 1 which is [(4chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.
 33. A compound according to claim 1 which is 4-(4butoxy-benzenesulfonyl)-1-(4 methylbenzyl)-piperidine-4f carboxylic acid hydroxamide or a pharmaceutical salt thereof.
 34. A compound according to claim 1 which is 4-(4butoxy-benzenesulfonyl)-1-(4cyano benzyl)-piperidine~carboxylic acid hydroxamide or a pharmaceutical salt thereof.
 35. A compound according to claim 1 which is 4-(4-Butoxy-benzenesulfonyl)-1-pyridin4 ylmethyl-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.
 36. A compound according to claim 1 or a pharmaceutically acceptable salt thereof which is selected from the group of compounds consisting of: 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide, 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-butyl-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide, 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidineAcarboxylic acid hydroxyamide, 1-isopropyl(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-benzyl1(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyaniide, 1-5 -1-(4fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)-piperidineAcarboxylic acid hydroxyamide, 1-(4-fluoro-benzy])4-(4-butoxy-benzenesulfonyl)-piperidinencarboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid hydroxyaride, 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine~carboxylic acid hydroxyamide, 4(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, and 4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy amide.
 37. A method of inhibiting pathological changes mediated by matix metalloproteinases in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound of the formula

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; cycloallyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵; or heteroaryl-(CH₂)0₆- wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R⁵; A is —S—, —SO— or SO₂—; R² and R³ , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionally having one or two double bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵; R⁵ is H, C₇-C₁-1 aroyl, C₂-C₆ alkanoyl, CI to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ .alynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl, S(0),-C₁-C₆ alkyl, S(0),-aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, -NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁l-6 alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10,membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, wherein C₁-C₆ alkyl is straig,ht or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; R⁶ is H, C₁ to C₈ alkyl optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, C, to C₆ perfluoro alkyl, S(0)n-C₁-C₆ alkyl S(0), aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, CI6 alky, Cl6 alkoxy, or hydroxy; and R⁷ is C Ijl aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alky, S(0)n-C₁-C₆-alyl, S(0)n-aryl where n is 0, 1 or 2; COO—C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃, SO2Nlheteroaryl, SO2NHCOaryl, CONHSO—C₁-C₆-alkyl, CONHSO₂aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—Cl1C₆ alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalklI or bicycloalkyl group is optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C₁-C₆ alkyl, optionally substituted with one or two groups selected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkyl where R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
 38. A method according to claim 37 wherein the condition treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, or periodontal disease.
 39. A method according to claim 37 wherein the condition treated is age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesislneovascularization and corneal graft rejection.
 40. A method of inhibiting pathological changes mediated by TNF-cA converting enzyme TACE) in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a TACE inhibiting compound of the formula

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵; or heteroaryl-(CH₂)6- wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionally having one or two double bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple'bonds, optionally substituted with one or two groups selected independently from R⁵; phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵; C₃ to C₈ cycloakl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵; R⁵ is H, C₇Cl, aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alky, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁c₆ alkoxyaryl, C₁c₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-Cl_(2 perfluoro alkyl, S()0)n-C₁-C₆ alkyl, S(0),-aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, -NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NIheteroaryl,SO2NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH2, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, wherein C₁l alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; R⁶ is H, C, to C₈ alky optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, C, to C₆ perfluoro alkyl, S(0)n-Cl6 alkyl S(0), aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and R⁷ is C₇-CII aroyl, CC₆ alkanoyl, C₁-C₁₂ penluoro alil, S(0)n-C₁-C₆-alkyl, S(0)n-aryl where n is 0, 1 or 2; COO—C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO—C l-C₆-alkyl, CONHSO₂aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, CC₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—Cl16 akyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently. from R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C IC₆ alkyl, optionally substituted with one or two groups selected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C,-alkyl where R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposed nitrogen forms a. 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
 41. The method according to claim 40 wherein the condition treated is rheumatoid artritis, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection.
 42. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound according to the formula

wherein: R¹ is allyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle contaiing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵; or heteroaryl-(CH,)₀-6— wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionally having one or two double bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; phenyl or naphthyl optionally substituted with one or two groups selected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, optionally substituted with one or two groups selected independently from R⁵; R⁵ is H, C₇Cl aroyl, C₂-C₆ alkanoyl, C₁ to C₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alyloxy, C₁₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-Cl₂ perfluoro alkyl, S(0)n-C₁-C₆ alkyl, S(0)n-aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCO0aryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, -NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ al, CONHSO₂aryl, NH2, OH, aryl, heteroaryl, C₃ to Cg cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR⁷, wherein Cl ₆ Aalyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; CS to C₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(0),-C₁-C₆ alkyl S(0)n aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, arino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and R⁷ is C₇-C₁, aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl, S(0)n-C₁-C₆-alkyl, S(0)r aryl where n is 0, 1 or 2; COO—C₁-C₆-alkyl, CO0aryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF3, SO2NHheteroaryl, SO₂NHCOaryl, CONHSO—C₁-C₆-alkyl, CONHSO₂aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; heteroarylallyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R⁵; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R⁵; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C₁-C₆ alkyl, optionally substituted with one or two groups selected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R? are independently selected from C₁-C₆ alkyl or Rs and R⁹ together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; 